Bicyclic derivatives of azabicyclic carboxamides, preparation thereof and therapeutic use thereof

ABSTRACT

The disclosure relates to compounds of formula (I): 
                         
wherein X 1 , X 2 , X 3 , X 4 , Y, n, A, and W are as defined in the disclosure, or a salt thereof, or a hydrate or solvate thereof, and to processes for the preparation of these compounds and the therapeutic use thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of application Ser. No.12/840,661 filed Jul. 21, 2010, which is a continuation ofPCT/FR2009/000051, filed Jan. 20, 2009 Documents WO2006/024776,WO2006/072736, WO2007/010144 and WO2007/010138 describe bicycliccarboxamide derivatives with in vitro and in vivo antagonist or agonistactivity on receptors of TRPV1 (or VR1) type.

There is still a need to find novel ligands for receptors of TRPV1 type,which are improved in terms of functional activity, metabolic profileand/or safety profile.

The present invention satisfies this need by providing azabicycliccarboxamide derivatives that have in vitro and in vivo antagonist oragonist activity on receptors of TRPV1 (or VR1) type.

A first subject of the invention concerns the compounds corresponding tothe general formula (I) hereinbelow.

Another subject of the invention concerns processes for preparing thecompounds of general formula (I).

Another subject of the invention concerns the use of the compounds ofgeneral formula (I) especially in medicaments or in pharmaceuticalcompositions.

The compounds of the invention correspond to the general formula (I):

in which:

X₁, X₂, X₃ and X₄ represent, independently of each other, a nitrogenatom or a group C—R₁;

it being understood that when one from among X₁, X₂, X₃ and X₄represents a nitrogen atom, the others correspond to a group C—R₁;

W represents an oxygen or sulfur atom;

n is equal to 0, 1, 2 or 3;

Y represents an aryl or a heteroaryl optionally substituted with one ormore groups chosen from a halogen atom, a group C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,hydroxyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxy, cyano,C(O)NR₄R₅, nitro, NR₄R₅, C₁-C₆-thioalkyl, thiol, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, SO₂NR₄R₅, NR₆C(O)R₇, NR₆SO₂R₈, C(O)NR₄R₅,OC(O)NR₄R₅, —Si—(C₁-C₆-alkyl)₃, —SF₅, aryl-C₁-C₅-alkylene or aryl,heteroaryl-C₁-C₅-alkylene or heteroaryl; the groups C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy and C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—being optionally substituted with a hydroxyl group, C₁-C₆-alkoxy orNR₄R₅, the aryl and heteroaryl groups being optionally substituted withone or more substituents R₉, which may be identical to or different fromeach other;

A represents the group of formula:

Z₁, Z₂, Z₃ and Z₄ represent, independently of each other, a nitrogenatom, a carbon atom or a group C—R₂,

at least one from among Z₁, Z₂, Z₃ and Z₄ corresponding to a nitrogenatom and

one from among Z₁, Z₂, Z₃ and Z₄, corresponding to a carbon atom, beingbonded to the nitrogen atom of the amide or of the thioamide of formula(I);

Ra and Rb form, together with the carbon atoms that bear them,

either a partially unsaturated cycloalkyl, or an aryl;

or a heterocycle, or a heteroaryl, which is 5- to 7-membered, comprisingfrom 1 to 3 heteroatoms chosen from O, S and N;

it being understood that when Ra and Rb together form, with the carbonatoms that bear them, a 5-membered ring, this ring comprising a nitrogenatom and carbon atoms, this ring being partially saturated orunsaturated, is excluded;

this partially unsaturated cycloalkyl, this aryl, this heterocycle orthis heteroaryl possibly being substituted with one or more substituentsR₃;

R₁ is chosen from a hydrogen atom, a halogen atom and a groupC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl,aryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl,heteroaryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl,heteroarylthio-C₁-C₆-alkyl, aryl-C₁-C₃-alkylene-thio-C₁-C₆-alkyl,heteroaryl-C₁-C₃-alkylene-thio-C₁-C₆-alkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₄R₆, nitro, NR₄R₆, C₁-C₆-thioalkyl,C₃-C₇-cycloalkylthio, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-thio,—S(O)—C₁-C₆-alkyl, —S(O)—C₃-C₇-cycloalkyl,—S(O)—C₁-C₃-alkylene-C₃-C₇-cycloalkyl, C₁-C₆-alkyl-S(O)₂—,C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, SO₂NR₄R₆, —Si—(C₁-C₆-alkyl)₃,—SF₅, NR₆C(O)R₇, NR₆SO₂R₈, C(O)NR₄R₅, OC(O)NR₄R₆, aryl, heteroaryl,aryl-C₁-C₅-alkylene, heteroaryl-C₁-C₅-alkylene, aryloxy, arylthio,heteroaryloxy or heteroarylthio; the heteroaryl or aryl groups beingoptionally substituted with one or more substituents R₉, which may beidentical to or different from each other;

R₂ represents a hydrogen atom, a halogen atom or a group C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-O—,hydroxyl, thiol or C₁-C₆-fluoroalkoxy;

R₃ represents, when it is borne by a carbon atom, a hydrogen atom or ahydroxyl, thiol, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-alkoxy-C₁-C₃-alkylene, C₃-C₇-cycloalkyloxy-C₁-C₃-alkylene,C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy-C₁-C₃-alkylene, C(O)NR₄R₆,C(O)O—C₁-C₆-alkyl, CO₂H, oxo or thio group; the groups C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-alkoxy-C₁-C₃-alkylene, C₃-C₇-cycloalkyloxy-C₁-C₃-alkylene andC₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy-C₁-C₃-alkylene possibly beingsubstituted with a hydroxyl group, C₁-C₆-alkoxy, —OC(O)—C₁-C₆-alkyl orNR₄R₅;

or

R₃ represents, when it is borne by a nitrogen atom, a hydrogen atom or agroup C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, aryl-C(O)—, C₁-C₆-alkyl-C(O)—,C₃-C₇-cycloalkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—,C₁-C₆-fluoroalkyl-C(O)—, aryl-S(O), C₁-C₅-alkyl-S(O)—,C₁-C₆-fluoroalkyl-S(O)—, aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—,C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, C₁-C₆-alkyl-O—C(O)—,aryl-C₁-C₃-alkyl-O—C(O)—, C₃-C₇-cycloalkyl-O—C(O)—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-O—C(O)—, C₁-C₆-fluoroalkyl-O—C(O)—,aryl-O—C(O)—, heteroaryl-O—C(O)—, heteroaryl or aryl; the heteroaryl andaryl groups being optionally substituted with one or more substituentsR₉, which may be identical to or different from each other; the groupsC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene andC₁-C₆-fluoroalkyl possibly being substituted with a hydroxyl group,C₁-C₆-alkoxy or NR₄R₅;

R₄ and R₅, represent, independently of each other, a hydrogen atom or agroup C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,aryl-C₁-C₆-alkylene or aryl, or R₄ and R₅ together form, with thenitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,azepine, morpholine, thiomorpholine, piperazine or homopiperazine group;the group NR₄R₅ being optionally substituted with a group C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene,aryl, heteroaryl, aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—,C₁-C₆-fluoroalkyl-S(O)₂, C₃-C₇-cycloalkyl-S(O)₂—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, aryl-C(O)—, C₁-C₆-alkyl-C(O)—,C₃-C₇-cycloalkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—,C₁-C₆-fluoroalkyl-C(O)—, hydroxyl, C₁-C₆-alkyloxy, C₃-C₇-cycloalkyloxy,C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy, C₁-C₆-fluoroalkyl,aryloxy-C₁-C₆-alkylene, aryloxy, heteroaryloxy-C₁-C₆-alkylene orheteroaryloxy;

R₆ and R₇ represent, independently of each other, a hydrogen atom or agroup C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,aryl-C₁-C₆-alkylene or aryl; the aryl group being optionally substitutedwith one or more substituents chosen from a halogen atom and a groupC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy,C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy, C₁-C₆-fluoroalkoxy, nitro or cyano;

or R₆ and R₇ together form a 4- to 7-membered lactam comprising thenitrogen atom and the C(O) group that bear them;

R₈ represents a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene or aryl; the arylgroup being optionally substituted with one or more substituents chosenfrom a halogen atom and a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-fluoroalkoxy, nitro or cyano;

or R₆ and R₈ together form a 4- to 7-membered sultam comprising thenitrogen atom and the S(O)₂ group that bear them;

R₉ represents a halogen atom or a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy orC₁-C₆-fluoroalkoxy; these groups being optionally substituted with agroup OH, C₁-C₆-alkoxy or NR₄R₅; or alternatively R₉ represents a nitro,cyano or NR₄R₅ group.

In the compounds of general formula (I):

-   -   the sulfur atom(s) may be in oxidized form (S(O) or S(O)₂);    -   the nitrogen atom(s) may optionally be in oxidized form        (N-oxide).

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may thus exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers, and alsomixtures thereof, including racemic mixtures, form part of theinvention.

The compounds of formula (I) may exist in the form of bases or ofacid-addition salts. Such addition salts form part of the invention.

These solvents may be prepared with pharmaceutically acceptable acids,but the salts of other acids that are useful, for example, for purifyingor isolating the compounds of formula (I) also form part of theinvention.

The compounds of formula (I) may also exist in the form of hydrates orsolvates, i.e. in the form of associations or combinations with one ormore water molecules or with a solvent. Such hydrates and solvates alsoform part of the invention.

In the context of the present invention, the following definitionsapply:

-   -   a halogen atom: a fluorine, a chlorine, a bromine or an iodine;    -   C_(t)-C_(z): a carbon-based chain possibly containing from t to        z carbon atoms in which t and z may take values from 1 to 7; for        example, C₁-C₃ is a carbon-based chain possibly containing from        1 to 3 carbon atoms;    -   an alkyl: a linear or branched saturated aliphatic group.        Examples that may be mentioned include methyl, ethyl, propyl,        isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc.;    -   an alkylene: a linear or branched saturated divalent alkyl        group, for example a group C₁₋₃-alkylene represents a linear or        branched divalent carbon-based chain of 1 to 3 carbon atoms,        more particularly a methylene, ethylene, 1-methylthylene or        propylene;    -   a cycloalkyl: a saturated or partially unsaturated cyclic alkyl        group. Examples that may be mentioned include the groups        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl,        cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.;    -   a cycloalkyloxy: a radical —O-cycloalkyl in which the cycloalkyl        group is as defined previously;    -   a fluoroalkyl: an alkyl group, one or more hydrogen atoms of        which have been replaced with a fluorine atom;    -   an alkoxy: a radical —O-alkyl in which the alkyl group is as        defined previously;    -   a fluoroalkoxy: an alkoxy group, one or more hydrogen atoms of        which have been replaced with a fluorine atom;    -   a thioalkyl or alkylthio: a radical —S-alkyl in which the alkyl        group is as defined previously;    -   an aryl: a monocyclic or bicyclic aromatic group containing        between 6 and 10 carbon atoms. Examples of aryl groups that may        be mentioned include phenyl and naphthyl groups;    -   a heterocycle: a saturated or partially unsaturated 5- to        7-membered monocyclic group, comprising from 1 to 3 heteroatoms        chosen from O, S and N.    -   Examples of heterocycles that may be mentioned include        azetidinyl, piperidyl, azepinyl, morpholinyl, thiomorpholinyl,        piperazinyl, homopiperazinyl, dihydrooxazolyl, dihydrothiazolyl,        dihydroimidazolyl, dihydropyrrolyl or tetrahydropyridyl,        [1,3]dioxolyl, [1,3]dioxinyl, dihydro[1,4]dioxinyl,        dihydro[1,2]oxazinyl, dihydro[1,3]oxazinyl, dihydrooxazole,        dihydroisoxazole, dihydro[1,4]oxazinyl,        tetrahydro[1,3]oxazepinyl, tetrahydro[1,4]oxazepinyl,        tetrahydro[1,3]diazepinyl and tetrahydro[1,4]diazepinyl.    -   a heteroaryl: a 5- to 12-membered monocyclic or bicyclic        aromatic group containing from 1 to 5 heteroatoms chosen from O,        S and N.    -   Examples of monocyclic heteroaryls that may be mentioned include        imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl,        isoxazolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl,        triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl,        pyridazinyl and triazinyl.    -   Examples of bicyclic heteroaryls that may be mentioned include        indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzoxazolyl,        benzimidazolyl, indazolyl, benzothienyl, isobenzofuryl,        isobenzothiazolyl, pyrrolo[2,3-c]pyridyl, pyrrolo[2,3-b]pyridyl,        pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl,        pyrrolo[1,2-a]pyridyl, quinolyl, isoquinolyl, cinnolinyl,        quinazolinyl, quinoxalinyl, pyrrolo[1,2-a]imidazolyl,        imidazo[1,2-a]pyridyl, imidazo[1,2-a]pyridazinyl,        imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrimidinyl,        imidazo[1,2-a]pyrazinyl, imidazo[4,5-b]pyrazinyl,        imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl,        pyrazolo[2,3-a]pyridyl, pyrazolo[2,3-a]pyrimidinyl,        pyrazolo[2,3-a]pyrazinyl, thiazolo[5,4-b]pyridyl,        thiazolo[5,4-c]pyridyl, thiazolo[4,5-c]pyridyl,        thiazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl,        oxazolo[5,4-c]pyridyl, oxazolo[4,5-c]pyridyl,        oxazolo[4,5-b]pyridyl, isothiazolo[5,4-b]pyridyl,        isothiazolo[5,4-c]pyridyl, isothiazolo[4,5-c]pyridyl,        isothiazolo[4,5-b]pyridyl, isoxazolo[5,4-b]pyridyl,        isoxazolo[5,4-c]pyridyl, isoxazolo[4,5-c]pyridyl and        isoxazolo[4,5-b]pyridyl.    -   “oxo” means “═O”;    -   “thio” means “═S”.

Among the compounds of general formula (I) that are subjects of theinvention, a first subgroup of compounds is constituted by the compoundsfor which X₁, X₂, X₃ and X₄ represent, independently of each other, agroup C—R₁; R₁ being as defined in the general formula (I).

Among the compounds of general formula (I) that are subjects of theinvention, a second subgroup of compounds is constituted by thecompounds for which

X₁, X₂, X₃ and X₄ represent, independently of each other, a nitrogenatom or a group C—R₁;

it being understood that one from among X₁, X₂, X₃ and X₄ represents anitrogen atom,

the others representing a group C—R₁;

R₁ being as defined in the general formula (I).

Among the compounds of general formula (I) that are subjects of theinvention, a third subgroup of compounds is constituted by the compoundsfor which X₁, X₂ and X₃ represent a group C—R₁; X₄ represents a nitrogenatom;

R₁ being as defined in the general formula (I).

Among the compounds of general formula (I) that are subjects of theinvention, a fourth subgroup of compounds is constituted by thecompounds for which R₁ is chosen from a hydrogen atom, a halogen atomand a group C₁-C₆-fluoroalkyl or —Si(C₁-C₆-alkyl)₃.

Among the compounds of general formula (I) that are subjects of theinvention, a fifth subgroup of compounds is constituted by the compoundsfor which R₁ is chosen from a hydrogen atom, a fluorine atom and a groupCF₃ or Si(CH₃)₃.

Among the compounds of general formula (I) that are subjects of theinvention, a sixth subgroup of compounds is constituted by the compoundsfor which

X₁, X₂, X₃ and X₄ represent, independently of each other, a group C—R₁;R₁ is chosen from a hydrogen atom, a halogen atom and a groupC₁-C₆-fluoroalkyl or —Si—(C₁-C₆-alkyl)₃

Among the compounds of general formula (I) that are subjects of theinvention, a seventh subgroup of compounds is constituted by thecompounds for which

X₁, X₂ and X₃ represent a group C—R₁; X₄ represents a nitrogen atom;

R₁ is chosen from a hydrogen atom and a group C₁-C₆-fluoroalkyl.

Among the compounds of general formula (I) that are subjects of theinvention, an eighth subgroup of compounds is constituted by thecompounds for which n is equal to 1.

Among the compounds of general formula (I) that are subjects of theinvention, a ninth subgroup of compounds is constituted by the compoundsfor which

Y represents an aryl or a heteroaryl optionally substituted with one ormore groups chosen from a halogen atom and a group C₁-C₆-alkyl orC₁-C₆-fluoroalkyl.

Among the compounds of general formula (I) that are subjects of theinvention, a tenth subgroup of compounds is constituted by the compoundsfor which

Y represents a phenyl, a thiazolyl or a pyridyl, this group beingoptionally substituted with one or more groups chosen from a halogenatom and a group C₁-C₆-alkyl or C₁-C₆-fluoroalkyl.

Among the compounds of general formula (I) that are subjects of theinvention, an eleventh subgroup of compounds is constituted by thecompounds for which

Y represents a phenyl, a thiazolyl or a pyridyl, this group beingoptionally substituted with one or more groups chosen from a fluorineatom and a methyl group or CF₃.

Among the compounds of general formula (I) that are subjects of theinvention, a twelfth subgroup of compounds is constituted by thecompounds for which

Y represents a phenyl optionally substituted with one or more groupschosen from a fluorine atom and a methyl group or CF₃.

Among the compounds of general formula (I) that are subjects of theinvention, a thirteenth subgroup of compounds is constituted by thecompounds for which W represents an oxygen atom.

Among the compounds of general formula (I) that are subjects of theinvention, a fourteenth subgroup of compounds is constituted by thecompounds for which

Z₁, Z₂, Z₃ and Z₄ represent, independently of each other, a nitrogenatom, a carbon atom or a group C—R₂,

one from among Z₁, Z₂, Z₃ and Z₄ corresponding to a nitrogen atom and

one from among Z₁, Z₂, Z₃ and Z₄, corresponding to a carbon atom, beingbonded to the nitrogen atom of the amide or of the thioamide of formula(I);

and the two others from among Z₁, Z₂, Z₃ and Z₄ corresponding to a groupC—R₂;

R₂ being as defined in the general formula (I).

Among the compounds of general formula (I) that are subjects of theinvention, a fifteenth subgroup of compounds is constituted by thecompounds for which

Z₁, Z₂, Z₃ and Z₄ represent, independently of each other, a nitrogenatom, a carbon atom or a group C—R₂,

one from among Z₁, Z₂, Z₃ and Z₄ corresponding to a nitrogen atom and

one from among Z₁, Z₂, Z₃ and Z₄, corresponding to a carbon atom, beingbonded to the nitrogen atom of the amide or of the thioamide of formula(I);

and the two others from among Z₁, Z₂, Z₃ and Z₄ corresponding to a CHgroup.

Among the compounds of general formula (I) that are subjects of theinvention, a sixteenth subgroup of compounds is constituted by thecompounds for which

Ra and Rb together form, with the carbon atoms that bear them,

either a partially unsaturated cycloalkyl, or an aryl;

or a heterocycle, or a heteroaryl, which is 5- or 6-membered, comprisingone or two heteroatoms chosen from O, S and N;

it being understood that when Ra and Rb together form, with the carbonatoms that bear them, a 5-membered ring, this ring comprising a nitrogenatom and carbon atoms, this ring being partially saturated orunsaturated, is excluded;

this partially unsaturated cycloalkyl, this aryl, this heterocycle orthis heteroaryl possibly being substituted with one or more substituentsR₃;

R₃ being as defined in the general formula (I).

Among the compounds of general formula (I) that are subjects of theinvention, a seventeenth subgroup of compounds is constituted by thecompounds for which

Ra and Rb together form, with the carbon atoms that bear them,

either a partially unsaturated cycloalkyl, or an aryl;

or a heterocycle, or a heteroaryl, which is 5- or 6-membered, comprisingone or two heteroatoms chosen from O, S and N;

it being understood that when Ra and Rb together form, with the carbonatoms that bear them, a 5-membered ring, this ring comprising a nitrogenatom and carbon atoms, this ring being partially saturated orunsaturated, is excluded;

this partially unsaturated cycloalkyl, this aryl, this heterocycle orthis heteroaryl possibly being substituted with one or more substituentsR₃,

R₃ represents, when it is borne by a carbon atom, a hydrogen atom or ahydroxyl, C₁-C₆-alkyl or oxo group; the C₁-C₆-alkyl group possibly beingsubstituted with a hydroxyl or —OC(O)—C₁-C₆-alkyl group; or

R₃ represents, when it is borne by a nitrogen atom, a hydrogen atom or agroup C₁-C₆-alkyl.

Among the compounds of general formula (I) that are subjects of theinvention, an eighteenth subgroup of compounds is constituted by thecompounds for which

Ra and Rb together form, with the carbon atoms that bear them,

either a partially unsaturated cycloalkyl, or an aryl;

or a heterocycle, or a heteroaryl, which is 5- or 6-membered, comprisingone or two heteroatoms chosen from O, S and N;

it being understood that when Ra and Rb together form, with the carbonatoms that bear them, a 5-membered ring, this ring comprising a nitrogenatom and carbon atoms, this ring being partially saturated orunsaturated, is excluded;

this partially unsaturated cycloalkyl, this aryl, this heterocycle orthis heteroaryl possibly being substituted with one or more substituentsR₃;

R₃ represents, when it is borne by a carbon atom, a hydrogen atom or ahydroxyl, methyl or oxo group; the methyl groups possibly beingsubstituted with a hydroxyl or —OC(O)-tert-butyl group; or

R₃ represents, when it is borne by a nitrogen atom, a hydrogen atom or amethyl group.

Among the compounds of general formula (I) that are subjects of theinvention, a nineteenth subgroup of compounds is constituted by thecompounds for which A represents the group of formula:

in which A is chosen from the groups

these groups being optionally substituted with R₂ and R₃ as defined inthe general formula (I) hereinabove.

Among the compounds of general formula (I) that are subjects of theinvention, a twentieth subgroup of compounds is constituted by thecompounds for which A represents the group of formula:

in which A is chosen from the groups

these groups being optionally substituted with R₂ and R₃ as defined inthe general formula (I) hereinabove;

R₂ represents a hydrogen atom;

R₃ represents, when it is borne by a carbon atom, a hydrogen atom or ahydroxyl, C₁-C₆-alkyl or oxo group; the C₁-C₆-alkyl group possibly beingsubstituted with a hydroxyl or —OC(O)—C₁-C₆-alkyl group; or

R₃ represents, when it is borne by a nitrogen atom, a hydrogen atom or agroup C₁-C₆-alkyl.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-first subgroup of compounds is constituted by thecompounds for which A represents the group of formula:

in which A is chosen from the groups

these groups being optionally substituted with R₂ and R₃ as defined inthe general formula (I) hereinabove;

R₃ represents, when it is borne by a carbon atom, a hydrogen atom or ahydroxyl, methyl or oxo group; the methyl groups possibly beingsubstituted with a hydroxyl or —OC(O)-tert-butyl group; or

R₃ represents, when it is borne by a nitrogen atom, a hydrogen atom or amethyl group.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-second subgroup of compounds is constituted by thecompounds for which the definitions of X₁, X₂, X₃ and X₄, n, Y, W, Z₁,Z₂, Z₃, Z₄; Ra and Rb given hereinabove are combined.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-third subgroup of compounds is constituted by thecompounds for which

X₁, X₂, X₃ and X₄ represent, independently of each other, a group C—R₁;or alternatively X₁, X₂ and X₃ represent a group C—R₁; X₄ represents anitrogen atom;

R₁ is chosen from a hydrogen atom, a halogen atom and a groupC₁-C₆-fluoroalkyl or —Si—(C₁-C₆-alkyl)₃,

n is equal to 1;

Y represents an aryl or a heteroaryl optionally substituted with one ormore groups chosen from a halogen atom and a group C₁-C₆-alkyl orC₁-C₆-fluoroalkyl;

W represents an oxygen atom;

A represents the group of formula:

in which A is chosen from the groups

these groups being optionally substituted with R₂ and R₃ as defined inthe general formula (I) hereinabove;

R₂ represents a hydrogen atom;

R₃ represents, when it is borne by a carbon atom, a hydrogen atom or ahydroxyl, C₁-C₆-alkyl or oxo group; the C₁-C₆-alkyl group possibly beingsubstituted with a hydroxyl or —OC(O)—C₁-C₆-alkyl group; or

R₃ represents, when it is borne by a nitrogen atom, a hydrogen atom or agroup C₁-C₆-alkyl.

Among the compounds of general formula (I) that are subjects of theinvention, a twenty-fourth subgroup of compounds is defined such that

the compounds for which

X₁, X₂, X₃ and X₄ represent, independently of each other, a group C—R₁;

R₁ is chosen from a hydrogen atom, a halogen atom and a groupC₁-C₆-alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-akoxy, C₁-C₆-fluoroalkoxy, NR₄R₆,C₁-C₆-thioalkyl, phenyl or isoxazolyl; the phenyl group being optionallysubstituted with one or more substituents R₉, which may be identical toor different from each other;

R₄ and R₅, represent, independently of each other, a hydrogen atom or agroup C₁-C₆-alkyl,

W represents an oxygen atom;

n is equal to 0;

Y represents a phenyl optionally substituted with one or moresubstituents R₉, which may be identical to or different from each other;or Y represents an isoxazole;

R₉ represents a halogen atom or a group C₁-C₆-alkyl, C₁-C₆-alkoxy orcyano;

A represents the group D:

in which

L represents a hydrogen atom, a halogen atom or a group C₁-C₄-alkoxy;

the 5-membered ring is partially saturated or unsaturated; J representsN or C═O; E and G represent, independently of each other, an oxygen orsulfur atom, or a group C═O, CH₂ or N—R′; R′ represents a hydrogen atomor a group C₁-C₄-alkyl or aryl-C(O)—, the aryl group being optionallysubstituted with one or more groups C₁-C₆-alkyl;

are excluded.

Among the compounds of general formula (I) that are subjects of theinvention, one sub-family is represented by the compounds of generalformula (I′) for which: R₃ represents, when it is borne by a carbonatom, a hydrogen atom or a hydroxyl, thiol, C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-alkoxy-C₁-C₃-alkylene, C₃-C₇-cycloalkyloxy-C₁-C₃-alkylene,C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy-C₁-C₃-alkylene, C(O)NR₄R₅,C(O)O—C₁-C₆-alkyl, CO₂H, oxo or thio group; the groups C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-alkoxy-C₁-C₃-alkylene, C₃-C₇-cycloalkyloxy-C₁-C₃-alkylene andC₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy-C₁-C₃-alkylene possibly beingsubstituted with a hydroxyl group, C₁-C₆-alkoxy or NR₄R₅.

Among the compounds of general formula (I′) that are subjects of theinvention, a first subgroup of compounds is constituted by the compoundsfor which X₁, X₂, X₃ and X₄ represent, independently of each other, agroup C—R₁; and R₁ is chosen from a hydrogen atom and a halogen atom,more particularly a fluorine atom.

Among the compounds of general formula (I′) that are subjects of theinvention, a second subgroup of compounds is constituted by thecompounds for which n is equal to 1 and Y represents an aryl, moreparticularly a phenyl, optionally substituted with one or more halogenatoms, more particularly fluorine atoms.

Among the compounds of general formula (I′) that are subjects of theinvention, a third subgroup of compounds is constituted by the compoundsfor which W represents an oxygen atom.

Among the compounds of general formula (I′) that are subjects of theinvention, a fourth subgroup of compounds is constituted by thecompounds for which A represents the group of formula:

in which A is chosen from the groups

these groups being optionally substituted with R₂ and R₃ as defined inthe general formula (I) hereinabove.

Among the compounds of general formula (I′) that are subjects of theinvention, a fifth subgroup of compounds is constituted by the compoundsfor which

X₁, X₂, X₃ and X₄ represent, independently of each other, a group C—R₁;and R₁ is chosen from a hydrogen atom and a halogen atom, moreparticularly a fluorine atom;

n is equal to 1;

Y represents an aryl, more particularly a phenyl, optionally substitutedwith one or more halogen atoms, more particularly fluorine atoms;

W represents an oxygen atom;

A represents the group of formula:

in which A is chosen from the groups

these groups being optionally substituted with R₂ and R₃ as defined inthe general formula (I) hereinabove.

Among the compounds of general formula (I) that are subjects of theinvention, mention may be made especially of the following compounds:

-   1    N-(2,3-Dimethyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide;-   2    N-(2-Methylthiazolo[5,4-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;-   3    N-(Thiazolo[5,4-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;-   4    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide;-   5    N-(Quinol-3-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;-   6    N-(2-Hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;-   7    N-(3-Methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;-   8    N-(2,3-Dimethyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-fluoro-phenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   9    N-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide;-   10    N-(4-Methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide;-   11    N-(2-Methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;-   12    N-(1-Methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;-   13    [6-[[[5-Fluoro-1-[(3-fluorophenyl)methyl]-1H-indol-2-yl]carbonyl]amino]thiazolo-[5,4-b]pyrid-2-yl]methyl    2,2-dimethylpropanoate;-   14    N-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyrid-7-yl))-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide;-   15    N-(6-Hydroxy-5,6,7,8-tetrahydroquinol-3-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;-   16    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-methyl-phenyl)methyl]-1H-indole-2-carboxamide;-   17    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trifluoromethyl-1-[(3-methyl-phenyl)methyl]-1H-indole-2-carboxamide;-   18    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(3-methyl-phenyl)methyl]-1H-indole-2-carboxamide;-   19    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[(3-methylphenyl)-methyl]-1H-indole-2-carboxamide;-   20    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide;-   21    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide;-   22    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide;-   23    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide;-   24    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   25    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide;-   26    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide;-   27    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trifluoromethyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide;-   28    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(pyrid-4-yl)-methyl]-1H-indole-2-carboxamide;-   29    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide;-   30    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   31    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide;-   32    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[[(3-trifluoro-methyl)phenyl]methyl]-1H-indole-2-carboxamide;-   33    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[[(3-trifluoromethyl)-phenyl]methyl]-1H-indole-2-carboxamide;-   34    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[[(3-trifluoro-methyl)phenyl]methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   35    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[[(3-trifluoro-methyl)phenyl]methyl]-1H-indole-2-carboxamide;-   36    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-methyl-phenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   37    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(3-methyl-phenyl)methyl]-1H-indole-2-carboxamide;-   38    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[[(3-trifluoro-methyl)phenyl]methyl]-1H-indole-2-carboxamide;    and-   39    N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trifluoromethyl-1-[[(3-trifluoro-methyl)phenyl]methyl]-1H-indole-2-carboxamide.

In the text hereinbelow, the term “leaving group” means a group that canbe readily cleaved from a molecule by breaking a heterolytic bond, withloss of an electron pair. This group may thus be readily replaced byanother group during a substitution reaction, for example. Such leavinggroups are, for example, halogens or an activated hydroxyl group such asa methanesulfonate, benzenesulfonate, p-toluenesulfate, triflate,acetate, etc. Examples of leaving groups and references for preparingthem are given in “Advances in Organic Chemistry”, J. March, 5thEdition, Wiley Interscience, 2001.

In the text hereinbelow, the term “protecting group” means a group thatcan be momentarily incorporated into a chemical structure for thepurpose of temporarily inactivating a part of the molecule during areaction, and which may be readily removed in a subsequent syntheticstep. Examples of protecting groups and references concerning theirproperties are given in T. W. Greene, P. G. M. Wutz, 3rd Edition, WileyInterscience 1999.

In accordance with the invention, the compounds of general formula (I)may be prepared according to the process illustrated by the generalscheme 1 below:

The compounds (I) may be obtained by reacting a compound of generalformula (II), in which B corresponds to a hydroxyl group and X₁, X₂, X₃,X₄, n, Y and W are as defined in the general formula (I) hereinabove,with an amine of general formula (III), in which Z₁, Z₂, Z₃, Z₄, Ra andRb are as defined in the general formula (I) hereinabove and Dcorresponds to an amino group, in the presence of a coupling agent suchas a dialkylcarbodiimide,[(benzotriazol-1-yl)oxy][tris(pyrrolidino)]phosphoniumhexafluoro-phosphate, diethyl cyanophosphonate or any other couplingagent known to those skilled in the art, optionally in the presence of abase such as triethylamine, in a solvent, for instancedimethylformamide.

Moreover, the compounds (I) may be obtained by reacting a compound ofgeneral formula (II), in which B represents a group C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy- oraryl-C₁-C₃-alkylenoxy and X₁, X₂, X₃, X₄, n, Y and W are as defined inthe general formula hereinabove, with an amide of the compound ofgeneral formula (III), in which Z₁, Z₂, Z₃, Z₄, Ra and Rb are as definedin the general formula (I) hereinabove and D corresponds to an aminogroup, in a refluxing solvent such as toluene. The aluminium amide ofthe compound of general formula (III) is prepared via the prior actionof trimethylaluminium on the amines of general formula (III).

The compounds (I) may also be obtained by reacting a compound of generalformula (II), in which B corresponds to a chlorine atom and X₁, X₂, X₃,X₄, n, Y and W are as defined in the general formula (I) hereinabove,with an amine of general formula (III), in which Z₁, Z₂, Z₃, Z₄, Ra andRb are as defined in the general formula (I) hereinabove and Dcorresponds to an amino group, by reaction in solution in a solvent suchas dichloromethane or toluene. The compounds of general formula (II) inwhich B corresponds to a chlorine atom are prepared from compounds ofgeneral formula (II) in which B corresponds to a hydroxyl group, byreaction with a reagent such as thionyl chloride or oxalyl chloride,optionally in the presence of a base such as triethylamine, in solutionin a solvent such as dichloromethane.

Starting with compounds of general formula (II), in which B representsan NH₂ group, W represents an oxygen atom and X₁, X₂, X₃, X₄, n and Yare as defined in the general formula (I) hereinabove, the compound ofgeneral formula (I) may be obtained by reaction with the compound ofgeneral formula (III), in which Z₁, Z₂, Z₃, Z₄, Ra and Rb are as definedin the general formula (I) hereinabove and D corresponds to a leavinggroup as defined hereinabove, such as a bromine atom or a triflategroup, for example according to a method similar to that described in J.Am. Chem. Soc. 2001, 123 (31), 7727, or according to methods describedin the literature or known to those skilled in the art, in the presenceof a copper salt in catalytic amount, in the presence of a catalyticamount of a copper ligand, such as a diamine, the whole in the presenceof a base such as potassium carbonate, in a solvent such as dioxane.

In Scheme 1, the compounds of general formula (I) and the otherreagents, when their mode of preparation is not described, arecommercially available, are described in the literature or are preparedby analogy with processes described in the literature (D. KnittelSynthesis 1985, 2, 186; T. M. Williams J. Med. Chem. 1993, 36 (9), 1291;JP2001-151771 A2, WO2006/024776, WO2006/072736, WO2007/010144,WO2007/010138 or WO2007/088277, for example).

The compounds of general formula (III), when their mode of preparationis not described, are commercially available, are described in theliterature or are prepared by analogy with processes described in theliterature (Tetrahedron Lett. 1987, 1589, Synthesis 2005, 15, 2503,Synthesis 2008, 2, 201, WO2006/040520).

The compounds of general formula (II) or (I), for which one from amongX₁, X₂, X₃ and X₄ corresponds to a carbon atom substituted with an alkylgroup, may be obtained via a coupling reaction, catalysed by a metalsuch as palladium or iron, performed on the corresponding compounds ofgeneral formula (II) or (I), substituted with a halogen atom, such aschlorine, in the presence, for example, of an alkylmagnesium halide oran alkylzinc halide, according to the methods described in theliterature (A. Furstner et al. J. Am. Chem. Soc. 2002, 124 (46), 13856;G. Queguiner et al., J. Org. Chem. 1998, 63 (9), 2892) for example, orknown to those skilled in the art.

The compounds of general formula (II) or (I), for which one from amongX₁, X₂, X₃ and X₄ corresponds to a carbon atom substituted with a cyano,aryl or heteroaryl group, may be obtained via a coupling reaction,catalysed with a metal such as palladium, performed on the correspondingcompounds of general formula (II) or (I), substituted, for example, witha bromine atom, in the presence of trimethylsilyl cyanide, anarylboronic acid or a heteroarylboronic acid, or via any other methoddescribed in the literature or known to those skilled in the art.

The compounds of general formula (I) or (II), for which one from amongX₁, X₂, X₃ and X₄ corresponds to a carbon atom substituted with a groupNR₄R₅, NR₆COR₇ or NR₆SO₂R₈, may be obtained from the correspondingcompounds of general formula (I) or (II), substituted, for example, witha bromine atom, via a coupling reaction with, respectively, an amine, anamide or a sulfonamide in the presence of a base, a phosphine and apalladium-based catalyst, according to methods described in theliterature or known to those skilled in the art.

The compounds of general formula (I) or (II) substituted with a groupC(O)NR₄R₅ may be obtained from the corresponding compounds of generalformula (I) or (II) substituted with a cyano group, according to methodsdescribed in the literature or known to those skilled in the art.

The compounds of general formula (I) or (II) substituted with a group—S(O)-alkyl or —S(O)₂-alkyl may be obtained via oxidation of thecorresponding compounds of general formula (II) or (I), substituted witha thioalkyl group, according to methods described in the literature orknown to those skilled in the art.

The compounds of general formula (II) or (I) substituted with a groupNR₄R₅, NR₆COR₇ or NR₆SO₂R₈ may be obtained from the correspondingcompounds of general formula (II) or (I), substituted with a nitrogroup, for example via reduction, followed by acylation orsulfonylation, according to methods described in the literature or knownto those skilled in the art.

The compounds of general formula (II) or (I) substituted with a groupSO₂NR₄R₅ may be obtained via a method similar to that described inPharmazie 1990, 45, 346, or according to methods described in theliterature or known to those skilled in the art.

The compounds of general formula (I) or (II) in which W represents asulfur atom may be obtained, for example, by reacting the correspondingcompounds of general formula (I) or (II), in which W represents anoxygen atom, with a reagent such as Lawesson's reagent.

The compounds of general formula (I) for which R₃ corresponds to aprotecting group borne by a nitrogen atom, such as an acetyl,ethoxycarbonyl or tert-butyloxycarbonyl group or a benzyloxycarbonylgroup, may be deprotected, according to chemical methods known to thoseskilled in the art, to give compounds of general formula (I) in which R₃is a hydrogen atom.

The compounds of general formula (I), for which R₃ corresponds to ahydroxyalkyl group, may be obtained from the compounds of generalformula (I) for which R₃ corresponds, for example, to an acetoxyalkyl orpivaloyloxyalkyl group according to chemical methods known to thoseskilled in the art, such as reaction with a base, for example aqueoussodium hydroxide solution, or reaction with an alkoxide, for example amethoxide, of a salt such as lithium or sodium, in an alcoholic solventsuch as methanol or ethanol, or reaction with a reducing agent such assodium borohydride, in a solvent such as tetrahydrofuran.

Alternatively, the compounds of general formula (I) for which R₃corresponds to a hydroxyalkyl group may be obtained from the compoundsof general formula (III), in which D corresponds to an amino group andR₃ corresponds, for example, to a pivaloyloxyalkyl group, by reactionwith an organometallic reagent such as trimethylaluminium, followed bycoupling with a compound of general formula (II), in which B correspondsto a group C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy,C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy- or aryl-C₁-C₃-alkylenoxy and X₁, X₂,X₃, X₄, n, Y and W are as defined in the general formula (I)hereinabove, followed by a treatment in acidic aqueous medium.

The compounds of general formula (II) of Scheme 1, in which one fromamong X₁, X₂, X₃ and X₄ represents a group C—R₁ in which R₁ correspondsto a group —Si—(C₁-C₆-alkyl)₃ and B represents a group C₁-C₆-alkoxyl,may be obtained, for example, according to the methods illustrated inScheme 2.

According to this method, the compounds of general formula (II), definedsuch that n is equal to 1, 2 or 3, are obtained by reaction of thecorresponding compounds (VI) with a reagent (VIII), in which LGrepresents a leaving group such as a chlorine, bromine or iodine atomand n is equal to 1, 2 or 3. The reaction for the formation of thecompounds of general formula (II) may be performed in the presence of abase such as sodium hydride or potassium carbonate, in a polar solventsuch as dimethylformamide, dimethyl sulfoxide or acetone (n=1: KolasaT., Bioorg. Med. Chem. 1997, 5 (3) 507, n=2: Abramovitch R., Synth.Commun., 1995, 25 (1), 1).

When the compound of general formula (VIII) is defined such that n isequal to 1, 2 or 3 and LG represents a hydroxyl group, the compounds ofgeneral formula (II) may be obtained by reacting the compound of generalformula (VI) with a compound of general formula (VIII) in the presenceof a phosphine, for instance triphenylphosphine, and a reagent, forinstance diethyl azodicarboxylate, dissolved in a solvent such asdichloromethane or tetrahydrofuran (O. Mitsonobu, Synthesis, 1981,1-28).

Similarly, the compounds of general formula (II) may be obtained byreacting the compound of general formula (VI) with a compound of generalformula (VIII) in the presence of a phosphine supported on a resin andof a reagent such as, for example, diisopropyl azodicarboxylate,dissolved in a solvent such as dichloromethane or tetrahydrofuran

When the compound of general formula (VIII) is defined such that n isequal to 0 and LG represents a leaving group such as a chlorine, bromineor iodine atom, the reaction for formation of the compounds of generalformula (II) may be performed by application or adaptation of themethods described by S. L. Buchwald et al. (J. Am. Chem. Soc., 2001,123, 7727 and 2002, 124, 11684), preferably under an inert atmosphere inbasic medium, for example in the presence of potassium triphosphate, inthe presence of a copper salt such as copper iodide, optionally in thepresence of an additive such as N,N′-dimethylcyclohexane-1,2-diamine,the whole in an organic solvent such as toluene.

The compounds of general formula (VI) are prepared from aromatic orheteroaromatic aldehydes substituted with a silyl group of generalformula (IV), in which X₁, X₂, X₃ and X₄ are as defined in the generalformula (I) with one of them corresponding to a silyl group, by reactionwith an alkyl azidoacetate of general formula (VII) in which Brepresents a group C₁-C₆-alkoxyl, for instance ethyl azidoacetate, inthe presence of a base such as sodium ethoxide, in a solvent such asethanol or methanol, to give the alkyl 2-azidocinnamates of generalformula (V). These products are then converted into indole or azaindoleesters in a refluxing solvent, for example in xylene or toluene, byadaptation of the protocols described in the literature (Hemetsberger etal. Monatsh. Chem., 1969, 100, 1599 and 1970, 101, 161; P. Roy et al.,Synthesis., 2005, 16, 2751-2757; R. Guilard et al., J. Heterocyclic.Chem., 1981, 18, 1365-1377; W. Rees et al., J. Chem. Soc., Perkin Trans.1 1984, 2189-2196; P. Molina et al., J. Org. Chem., 2003, 68 (2),489-499; C. Moody et al., J. Chem. Soc., Perkin Trans. 1 1984,2189-2196; J. Sawyer et al., J. Med. Chem., 2005, 48, 893-896; D. TannerSynlett 2006, 18, 3140-3144).

Alternatively, the formation of the compounds of general formula (VI)may be obtained by decomposition of the alkyl 2-azidocinnamate ofgeneral formula (V), in the presence of a rhodium dimer complex, in asolvent such as toluene, at a temperature of between 25° C. and 60° C.,according to an adaptation of protocols described in the literature (TomG. Drivers et al., J. Am. Chem. Soc., 2007, 129, 7500-7501; J. Sawyer etal., J. Med. Chem., 2005, 48, 893-896).

The aromatic or heteroaromatic aldehydes substituted with a silyl groupof general formula (IV), when they are not commercially available, maybe obtained from the corresponding aromatic or heteroaromatic aldehydes,which are preferably masked in the form of an acetal, for example,substituted with a halogen atom such as a bromine or an iodine, in theposition at which the silyl group is to be introduced:

-   -   for example by reaction with a disilane such as        hexamethyldisilane, in the presence of a catalytic amount of a        metal complex, preferably a palladium complex, for instance        tetrakis(triphenylphosphine)palladium, without solvent or in a        solvent, preferably a polar solvent, for instance        hexamethylphosphoramide, in the presence of a base such as        potassium carbonate, at a temperature of between 20° C. and the        boiling point of the solvent (adaptation of the protocols        described in the literature: J. Babin et al. J. Organometall.        Chem., 1993, 446 (1-2), 135-138; E. Shirakawa et al., Chem.        Commun., 2000, 1895-1896; L. Goossen et al. Synlett, 2000,        1801-1803; H. Matsumoto et al., J. Organometall. Chem., 1975,        85, C1; FR 2 677 358).    -   for example by reaction with a disilane such as        hexamethyldisilane, in the presence of a strong base, for        instance hexamethylphosphorotriamide (HMPT), at a temperature        close to 20° C. (adaptation of the protocols described in the        literature: A. I. Meyers et al., J. Org. Chem., 1977, 42 (15),        2654-2655; K. Ishimaru et al., Heterocycles., 2001, 55 (8),        1591-1597).

The aromatic or heteroaromatic aldehydes substituted with a silyl groupof general formula (IV), when they are not commercially available, mayalso be obtained from the corresponding dihalo aromatic orheteroaromatic derivatives, such as a dibromo derivative, in theposition at which the silyl group is to be introduced, by exchange withan organometallic reagent, for instance n-butyllithium. The metallicaromatic or heteroaromatic derivatives thus formed may then react withorganohalosilanes or may be converted into formyl derivatives byadaptation of the methods described in the literature. The reaction ispreferably performed at low temperatures of between −110° C. and roomtemperature, in a solvent such as ether or THF (adaptation of theprotocols described in the literature: Bao-Hui Ye et al., Tetrahedron.,2003, 59, 3593-3601; P. Pierrat et al., Synlett 2004, 13, 2319-2322; K.T. Warner et al., Heterocycles 2002, 58, 383; D. Deffieux et al., J.Organometall. Chem., 1994, 13 (6), 2415-2422; WO2005/080328; S. G.Davies et al., J. Chem. Soc., Perkin Trans. 1 1991, 501; G. Queguiner etal., J. Org. Chem., 1981, 46, 4494-4497; G. Breton et al., Tetrahedron2000, 56 (10), 1349-1360; S. De Montis et al., Tetrahedron 2004, 60(17), 3915-3920; L. Buchwald et al., J. Am. Chem. Soc., 1998, 120,4960-4976).

According to another of its aspects, a subject of the invention is alsothe compounds of general formulae (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg) and (IIh), in which Me represents a methyl group and Etrepresents an ethyl group. These compounds are useful as intermediatesfor the synthesis of the compounds of formula (I).

The esters (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) and (IIh) areprepared according to the processes described in Examples 18, 22, 25,28, 31, 32, 35 and 37.

The examples that follow describe the preparation of certain compoundsin accordance with the invention. These examples are not limiting, andserve merely to illustrate the present invention. The numbers of theillustrated compounds refer to those in Table 1. The elementalmicroanalyses, the LC-MS analyses (liquid chromatography coupled to massspectrometry) and the IR or NMR spectrum confirm the structures of thecompounds obtained.

EXAMPLE 1 Compound 1N-(2,3-Dimethyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide1.1 5-Fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid

Aqueous sodium hydroxide solution, prepared from 1.15 g (28.92 mmol) ofsodium hydroxide pellets in 50 mL of water, is added to a solution of7.6 g (24.10 mmol) of ethyl5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO2006/024776) in241 mL of ethanol. The mixture is heated for 2 hours and thenconcentrated under reduced pressure. The resulting solid is taken up in200 mL of water. The solution is washed with twice 100 mL of ethylether, acidified by successive addition of small amounts of concentratedhydrochloric acid and then extracted with 200 mL of ethyl acetate. Theorganic phase is finally washed twice with 100 mL of water and once with50 mL of saturated sodium chloride solution, dried over magnesiumsulfate and concentrated under reduced pressure. After drying at 50° C.under reduced pressure, 6.4 g of the expected product are obtained inthe form of a solid, which is used without further purification in therest of the synthesis.

1.2N-(2,3-Dimethyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide(Compound 1)

To a solution, stirred at 20° C., of 0.25 g (0.87 mmol) of5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step1.1, 183 mg (0.96 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and129 mg (0.96 mmol) of 1-hydroxybenzotriazole (HOBT) in 8 mL of DMF areadded 130 microlitres (0.96 mol) of triethylamine and then 224 mg (1.13mmol) of 6-amino-2,3-dimethyl-3H-imidazo[4,5-b]pyridine hydrochloride(Ukrainskii Khimicheskii Zhurnal 1981, 47, 867). The reaction mixture isstirred for 8 hours at 20° C. and then concentrated under reducedpressure. The resulting product is taken up in 100 mL of water, and aprecipitate is collected by filtration and is purified by chromatographyon a column of silica, eluting with a mixture of dichloromethane andmethanol. The fractions containing the product are combined andevaporated to a quarter of their volume. 50 mL of n-heptane are added tothe solution, and a solid is collected by filtration and dried underreduced pressure. 150 mg of the expected product are thus isolated.

m.p.=274-275° C.

¹H NMR (DMSO-D₆), δ ppm: 10.59 (s, 1H); 8.59 (s, 1H); 8.3 (s, 1H); 7.6(m, 2H); 7.46 (s, 1H); 7.32 (m, 1H); 7.19 (m, 1H); 7.07 (m, 1H); 6.92(m, 2H); 5.91 (s, 2H); 3.78 (s, 3H); 2.6 (s, 3H).

EXAMPLE 2 Compound 2N-(2-Methylthiazolo[5,4-b]pyrid-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

The process is performed according to a method similar to that ofExample 1.2, starting with 0.5 g (1.74 mmol) of5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step1.1 and 0.345 g (2.09 mmol) of 6-amino-2-methylthiazolo[5,4-b]pyridine(Yakugaku Zasshi 1950, 70, 187). At the end of the reaction, the productis concentrated under reduced pressure and then taken up in 100 mL ofwater. A precipitate is collected by filtration, and is purified bychromatography on a column of alumina, eluting with a mixture ofdichloromethane and methanol. The resulting product is recrystallizedfrom methanol, and a solid is collected by filtration, and dried underreduced pressure. 340 mg of the expected product are thus isolated.

m.p.=264-265° C.

¹H NMR (DMSO-D₆), δ ppm: 10.85 (s, 1H); 8.9 (s, 1H); 8.67 (s, 1H); 7.61(m, 2H); 7.51 (s, 1H); 7.31 (m, 1H); 7.2 (m, 1H); 7.05 (m, 1H); 6.9 (m,2H); 5.9 (s, 2H); 2.87 (s, 3H).

EXAMPLE 3 Compound 3N-(Thiazolo[5,4-b]pyrid-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

The process is performed according to a method similar to that ofExample 1.2, starting with 0.32 g (1.11 mmol) of5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step1.1 and 0.2021 g (1.34 mmol) of 6-amino-thiazolo[5,4-b]pyridine(WO2007/100758). At the end of the reaction, the product is concentratedunder reduced pressure and then taken up in 100 mL of water. Aprecipitate is collected by filtration, and is purified bychromatography on a column of alumina, eluting with a mixture ofdichloromethane and methanol. The resulting product is recrystallizedfrom methanol, and a solid is collected by filtration and dried underreduced pressure. 340 mg of the expected product are thus isolated.

m.p.=250-251° C.

¹H NMR (DMSO-D₆), δ ppm: 10.9 (s, 1H); 9.57 (s, 1H); 9 (s, 1H); 8.98 (s,1H); 7.61 (m, 2H); 7.51 (s, 1H); 7.31 (m, 1H); 7.2 (m, 1H); 7.08 (m,1H); 6.92 (m, 2H); 5.91 (s, 2H).

EXAMPLE 4 Compound 13[6-[[[5-Fluoro-1-[(3-fluorophenyl)methyl]-1H-indol-2-yl]carbonyl]amino]thiazolo[5,4-b]pyrid-2-yl]methyl2,2-dimethylpropanoate 4.1 (6-Nitrothiazolo[5,4-b]pyrid-2-yl)methyl2,2-dimethylpropanoate

A mixture of 6 g (29.48 mmol) of 2-chloro-3,5-dinitropyridine and 7.74 g(44.22 mmol) of 2-amino-2-thioxoethyl pivalate in 50 mL of sulfolane isheated for 2 hours at 105° C. After this time, 150 mL of ethyl acetateare added to the mixture, and the organic phase is washed three timeswith 200 mL of water and then once with 100 mL of saturated sodiumchloride solution. The organic phase is then separated out, dried oversodium sulfate and then concentrated under reduced pressure. The productobtained is purified by chromatography on a column of silica, elutingwith a mixture of heptane and ethyl acetate. 1.45 g of a yellow solidare obtained.

¹H NMR (CDCl₃), δ ppm: 9.55 (d, 1H); 9.09 (d, 1H); 5.59 (s, 2H); 1.38(s, 9H).

4.2 (6-Aminothiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate

A mixture of 0.75 g (2.54 mmol) of(6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate,prepared in step 4.1, and 1.68 g (8.89 mmol) of tin chloride in 50 mL ofethyl acetate is stirred for 30 minutes at 50° C. After this time, thereaction mixture is poured into 100 mL of ice-cold water. The pH of theaqueous solution is neutralized by successive addition of sodiumhydroxide solution. The aqueous phase is then extracted with 3 times 50mL of ethyl acetate. The organic phases are combined, dried and thenconcentrated under reduced pressure. 0.7 g of a solid is thus obtained,which product is used without further purification in the rest of thesynthesis.

¹H NMR (CDCl₃), δ ppm: 8.05 (d, 1H); 7.42 (d, 1H); 5.37 (s, 2H); 1.21(s, 9H).

4.3[6-[[[5-Fluoro-1-[(3-fluorophenyl)methyl]-1H-indol-2-yl]carbonyl]amino]thiazolo-[5,4-b]pyrid-2-yl]methyl2,2-dimethylpropanoate (Compound 13)

240 microlitres (2.78 mmol) of oxalyl chloride are added, dropwise at 0°C., to a solution of 0.4 g (1.39 mmol) of5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid,prepared in step 1.1, in 10 mL of dichloromethane and 0.5 mL ofdimethylformamide. The mixture is stirred for 15 minutes at 0° C. andthen for 1 hour at 20° C. After this time, a further 120 microlitres(1.39 mmol) of oxalyl chloride are added and stirring is continued for30 minutes at 20° C. The reaction mixture is then concentrated underreduced pressure and taken up in 5 mL of tetrahydrofuran. 219microlitres of triethylamine and then a solution of 0.44 g (1.67 mmol)of (6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate,prepared in step 4.2, in 10 mL of tetrahydrofuran are added, under aninert atmosphere. The reaction mixture is stirred for 15 hours at 20° C.and for 1 hour at 40° C., and then concentrated under reduced pressureand taken up in 100 mL of water. The aqueous phase is extracted threetimes with 50 mL of ethyl acetate. The organic phases are combined,washed successively with 50 mL of saturated sodium hydrogen carbonatesolution and with 50 mL of saturated sodium chloride solution, and thendried over sodium sulfate and concentrated under reduced pressure. Theproduct thus obtained is purified on a column of alumina, eluting withdichloromethane. 0.15 g of the expected product is thus isolated.

m.p.=224-225° C.

¹H NMR (DMSO-D₆), δ ppm: 8.89 (s, 1H); 8.71 (s, 1H); 7.52 (m, 2H); 7.45(s, 1H); 7.29 (m, 1H); 7.15 (m, 1H); 7.00 (m, 1H); 6.9 (m, 1H); 6.81 (m,1H); 5.86 (s, 2H); 5.49 (s, 2H); 1.12 (s, 9H).

EXAMPLE 5 Compound 5N-(Quinol-3-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

1.19 mL (2.38 mmol) of a 2M solution of trimethylaluminium in tolueneare added dropwise to a solution, stirred at 0° C. under an inertatmosphere, of 0.274 g (1.9 mmol) of 3-aminoquinoline in 40 mL of drytoluene. The mixture is then stirred at 50° C. After 15 minutes, asolution of 0.5 g (1.59 mmol) of ethyl5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO2006/024776) in10 mL of toluene is added dropwise. 15 mL of 1N hydrochloric acidsolution and 100 mL of ethyl acetate are added to the mixture. Theorganic phase is separated out and then washed successively with 20 mLof 1N hydrochloric acid solution, 20 mL of water and 20 mL of saturatedsodium chloride solution, and then concentrated under reduced pressure.The product thus obtained is triturated in 10 mL of hot toluene. Aprecipitate is collected by filtration. After drying, 295 mg of theexpected product are thus isolated.

m.p.=244-246° C.

¹H NMR (CDCl₃), δ ppm: 10.91 (s, 1H); 9.15 (d, 1H); 8.88 (d, 1H); 8 (m,2H); 7.62 (m, 5H); 7.32 (m, 1H); 7.21 (m, 1H); 7.08 (m, 1H); 6.92 (m,2H); 5.95 (s, 2H).

EXAMPLE 6 Compound 4N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

50 mg (2.03 mmol) of sodium are added to 8 mL of methanol with stirringat 20° C. After 15 minutes, a solution of 0.15 g (0.28 mmol) of[6-[[[5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indol-2-yl]carbonyl]amino]thiazolo[5,4-b]pyrid-2-yl]methyl2,2-dimethylpropanoate (Compound 13), prepared in step 4.3, in 16 mL ofmethanol is added. Stirring is continued for 15 minutes at 20° C., andthe reaction mixture is then concentrated under reduced pressure andtaken up in 200 mL of molar ammonium chloride solution. The aqueousphase is extracted three times with 50 mL of ethyl acetate. The organicphases are combined, washed with 50 mL of saturated sodium chloridesolution and then dried over sodium sulfate and concentrated underreduced pressure. The product thus obtained is purified on a column ofsilica, eluting with a mixture of dichloromethane and methanol. 70 mg ofthe expected product are thus isolated.

m.p.=225-226° C.

¹H NMR (CDCl₃), δ ppm: 10.84 (s, 1H); 8.92 (d, 1H); 8.72 (d, 1H); 7.61(m, 2H); 7.5 (s, 1H); 7.35 (m, 1H); 7.2 (m, 1H); 7.08 (m, 1H); 6.92 (m,2H); 6.37 (m, 1H); 5.91 (s, 2H); 4.9 (s, 2H).

EXAMPLE 7 Compound 6N-(2-Hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide7.1 2-Hydroxymethyl-6-nitro-3-methyl-3H-imidazo[4,5-b]pyridine and3-methyl-6-nitro-3H-imidazo[4,5-b]pyridine

A mixture of 3.1 g (18.44 mmol) of 3-amino-5-nitro-2-methylaminopyridineand 3.5 g (46.09 mmol) of glycolic acid is heated at 150° C. After 75minutes, the mixture is cooled and then dissolved in 50 mL of 1Nhydrochloric acid. The pH of the aqueous phase is adjusted to 9 bysuccessive additions of concentrated sodium hydroxide, and the mixtureis then concentrated under reduced pressure. The resulting solid ispurified by chromatography on a column of silica, eluting with a mixtureof dichloromethane and methanol. 1.5 g of the expected product are thusisolated. This purification also allows 0.2 g of3-methyl-6-nitro-3H-imidazo[4,5-b]pyridine to be isolated.

2-Hydroxymethyl-6-nitro-3-methyl-3H-imidazo[4,5-b]pyridine

LCMS: [MH]⁺=209

¹H NMR (DMSO-D₆), δ ppm: 9.3 (d, 1H); 8.89 (d, 1H); 5.88 (m, 1H); 4.83(m, 2H); 3.95 (t, 3H).

3-Methyl-6-nitro-3H-imidazo[4,5-b]pyridine

LCMS: [MH]⁺=179

¹H NMR (DMSO-D₆), δ ppm: 9.31 (d, 1H); 8.95 (d, 1H); 8.79 (s, 1H); 3.95(t, 3H).

7.2 6-Amino-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyridine

A suspension of 0.5 g (2.4 mol) of2-hydroxymethyl-6-nitro-3-methyl-3H-imidazo[4,5-b]pyridine, prepared inthe preceding step, and 0.3 g of 10% palladium-on-charcoal is stirredfor 3 hours under 2.5 atm. of hydrogen. After this time, the suspensionis filtered through a pad of Celite and the filtrate is concentratedunder reduced pressure. 0.4 g of the expected product is thus isolated,and is used without further purification in the rest of the synthesis.

LCMS: [MH]*=179

7.3N-(2-Hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide(Compound 6)

Compound 6 is synthesized according to a process similar to thatdescribed in Example 1.2, starting with6-amino-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]-pyridine described inthe preceding step and5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic aciddescribed in step 1.1.

m.p.: 231-232° C.

¹H NMR (DMSO-D₆), δ ppm: 10.67 (s, 1H); 8.68 (s, 1H); 8.4 (s, 1H); 7.6(m, 2H); 7.48 (s, 1H); 7.33 (m, 1H); 7.18 (txd, 1H); 7.055 (txd, 1H);6.94 (m, 2H); 5.92 (s, 2H); 5.69 (t, 1H); 4.8 (d, 2H); 3.88 (s, 3H)

EXAMPLE 8 Compound 7N-(3-Methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide8.1 6-Amino-3-methyl-3H-imidazo[4,5-b]pyridine

This compound is prepared according to a process similar to thatdescribed in step 7.2, starting with3-methyl-6-nitro-3H-imidazo[4,5-b]pyridine prepared in step 7.1.

LCMS: [MH]⁺=149

8.3N-(3-Methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide(Compound 7)

Compound 7 is synthesized according to a process similar to thatdescribed in Example 1.2, starting with6-amino-3-methyl-3H-imidazo[4,5-b]pyridine, described in the precedingstep, and 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylicacid, described in step 1.1.

m.p.: 235-236° C.

¹H NMR (DMSO-D₆), δ ppm: 10.68 (s, 1H); 8.69 (s, 1H); 8.42 (m, 2H); 7.6(m, 2H); 7.49 (s, 1H); 7.32 (m, 1H); 7.19 (m, 1H); 7.06 (m, 1H); 6.92(m, 2H); 5.91 (s, 2H); 3.87 (s, 3H).

EXAMPLE 9 Compound 8N-(2,3-Dimethyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)-methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

This compound was prepared according to a process similar to thatdescribed in Example 1.2, starting with5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid (WO2008/093024).

m.p.: 274-275° C.

¹H NMR (DMSO-D₆), δ ppm: 10.75 (s, 1H); 8.83 (s, 1H); 8.76 (s, 1H); 8.55(s, 1H); 8.28 (s, 1H); 7.63 (s, 1H); 7.32 (m, 1H); 7.07 (m, 1H); 6.98(m, 2H); 6.01 (s, 2H); 3.76 (s, 3H); 2.6 (s, 3H).

EXAMPLE 10 Compound 9N-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide10.1 5-Fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

To a suspension, stirred at 20° C., of 2 g (6.96 mmol) of5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxylic acid,prepared in step 1.1, in 80 mL of dry toluene are added 5.08 mL (69.62mmol) of thionyl chloride. The reaction mixture is stirred for 2 hoursat reflux and is then concentrated under reduced pressure. The resultingproduct is taken up in 10 mL of dichloromethane, and this solution ispoured dropwise into a solution of 9.12 mL (69.62 mmol) of 30% aqueousammonia. The reaction mixture is stirred for 14 hours at 20° C. Afterthis time, a solid is collected by filtration, and is triturated in 50mL of diisopropyl ether. After filtering off and drying under reducedpressure, 0.58 g of the expected product is collected.

¹H NMR (DMSO-D₆), δ ppm: 8.11 (broad peak, 1H); 7.5 (m, 3H); 7.32 (m,1H); 7.25 (s, 1H); 7.09 (m, 2H); 6.89 (m, 2H); 5.91 (s, 2H).

10.2N-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide(Compound 9)

0.4 g (1.4 mmol) of the amide prepared in the preceding step, 0.31 g(1.47 mmol) of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 0.08 g(0.42 mmol) of copper iodide, 0.39 g (2.79 mmol) of potassium carbonateand 10 mL of dry dioxane are introduced into a pressure tube equippedwith a magnetic stirrer. The suspension is degassed, 53 mg (0.46 mmol)of trans-1,2-cyclohexanediamine are added, and the tube is heated at120° C. with stirring for 16 hours. After this time, 50 mL of ethylacetate and 50 mL of water are added to the medium. The aqueous phase isseparated out and then extracted with 2×30 mL of ethyl acetate. Theorganic phases are combined, washed with 50 mL of water, dried oversodium sulfate and then concentrated under reduced pressure. Theresulting product is purified by chromatography on a column of silica,eluting with a mixture of heptane and ethyl acetate, followed bycrystallization from a mixture of heptane and dichloromethane. 0.4 g ofthe expected product is thus isolated.

m.p.: 265-266° C.

¹H NMR (DMSO D₆), δ (ppm): 10.22 (s, 1H); 7.98 (s, 1H); 7.58 (m, 2H);7.34 (m, 3H); 7.18 (m, 1H); 7.06 (m, 1H); 6.91 (m, 2H); 6.58 (s, 1H);5.9 (s, 2H); 4.14 (m, 2H); 3.4 (m, 2H).

EXAMPLE 11 Compound 10N-(4-Methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide

This compound was prepared according to a process similar to thatdescribed in Example 10.2, starting with7-amino-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.

m.p.: 214-215° C.

¹H NMR (DMSO D₆), δ (ppm): 10.29 (s, 1H); 8.03 (s, 1H); 7.58 (m, 2H);7.34 (m, 3H); 7.18 (m, 1H); 7.05 (m, 1H); 6.91 (m, 2H); 5.9 (s, 2H);4.26 (m, 2H); 3.41 (m, 2H); 3.02 (s, 3H).

EXAMPLE 12 CN-(2-Methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide12.1 2-Methyl-6-nitro-3H-imidazo[4,5-b]pyridine

2.3 mL (24.33 mol) of acetic anhydride are added to a solution, stirredat 15° C., of 1.5 g (9.73 mmol) of 2,3-diamino-5-nitropyridine in 15 mLof acetic acid. After stirring for 15 minutes at room temperature, themixture is heated at 110° C. for 2 hours and then at 140° C. for 7hours. The resulting mixture is concentrated under reduced pressure andtaken up in 100 mL of water. A precipitate is collected by filtration.After purification by chromatography on a column of silica, 0.4 g of theexpected product is obtained.

LCMS: [MH]⁺=179

¹H NMR (DMSO D₆), δ (ppm): 9.2 (d, 1H); 8.7 (d, 1H); 2.62 (s, 3H).

12.2 6-Amino-2-methyl-3H-imidazo[4,5-b]pyridine

This compound is prepared according to a process similar to thatdescribed in step 7.2, starting with2-methyl-6-nitro-3H-imidazo[4,5-b]pyridine prepared in step 12.1.

LCMS: [MH]⁺=149

¹H NMR (DMSO D₆), δ (ppm): 7.7 (d, 1H); 6.99 (d, 1H); 2.4 (s, 3H).

12.3N-(2-Methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide(Compound 11)

This compound was prepared according to a process similar to thatdescribed in Example 1.2, starting with5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid,prepared in Example 1.1 and 6-amino-2-methyl-3H-imidazo[4,5-b]pyridine,prepared in the preceding step.

m.p.: 299-300° C.

¹H NMR (DMSO D₆), δ (ppm): 12.37 (s, 1H); 10.6 (s, 1H); 8.53 (s, 1H);8.29 (m, 1H); 7.61 (dxd, 1H); 7.58 (dxd, 1H); 7.46 (s, 1H); 7.33 (m,1H); 7.18 (txd, 1H); 7.05 (txd, 1H); 6.94 (m, 2H); 5.9 (s, 2H); 2.48 (s,3H).

EXAMPLE 13 Compound 12N-(1-Methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide13.1 7-Bromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

0.16 mL (2.62 mmol) of methyl iodide is added to a suspension of 0.5 g(2.18 mol) of 7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine,0.24 g (1.09 mmol) of benzyltriethylammonium chloride and 0.75 g (5.46mmol) of potassium carbonate in 25 mL of acetonitrile. The mixture isstirred for 6 hours at 60° C. After this time, a precipitate is removedby filtration. The filtrate is concentrated under reduced pressure andthe resulting solid is taken up in 15 mL of dichloromethane and thenwashed successively with 20 ml of water, 10 mL of 0.1N hydrochloric acidsolution, 10 mL of saturated sodium hydrogen carbonate solution and then10 mL of water. After drying over sodium sulfate, the solution isfinally concentrated under reduced pressure to give the expectedproduct, which is used without further purification in the followingstep.

¹H NMR (DMSO D₆), δ (ppm): 7.98 (d, 1H); 7.79 (d, 1H); 4.9 (s, 2H); 3.29(s, 3H).

13.2N-(1-Methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide(Compound 12)

This compound was prepared according to a process similar to thatdescribed in Example 10.2, starting with7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine preparedin the preceding step.

m.p.: 248-250° C.

¹H NMR (DMSO D₆), δ (ppm): 10.61 (s, 1H); 8.23 (d, 1H); 7.91 (d, 1H);7.59 (txd, 2H); 7.46 (s, 1H); 7.33 (m, 1H); 7.19 (txd, 1H); 7.06 (txd,1H); 6.9 (m, 2H); 5.91 (s, 2H); 4.87 (s, 2H); 3.25 (s, 3H).

EXAMPLE 14 Compound 14N-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyrid-7-yl))-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

This compound was prepared according to a process similar to thatdescribed in Example 10.2, starting with7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (WO2003/087098).

m.p.: 224-225° C.

¹H NMR (DMSO D₆), δ (ppm): 10.49 (s, 1H); 8.1 (s, 1H); 7.71 (s, 1H);7.59 (m, 2H); 7.41 (s, 1H); 7.31 (m, 1H); 7.18 (m, 1H); 7.04 (m, 1H);6.91 (m, 2H); 5.89 (s, 2H); 4.4 (m, 2H); 3.88 (m, 2H).

EXAMPLE 15 Compound 15N-(6-Hydroxy-5,6,7,8-tetrahydroquinol-3-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

This compound was prepared according to a process similar to thatdescribed in Example 1.2, starting with3-amino-6-hydroxy-5,6,7,8-tetrahydroquinoline (WO2007/100758).

m.p.: 204-206° C.

¹H NMR (DMSO D₆), δ (ppm): 10.51 (s, 1H); 8.61 (s, 1H); 7.89 (s, 1H);7.59 (m, 2H); 7.43 (s, 1H); 7.32 (m, 1H); 7.19 (m, 1H); 7.04 (m, 1H);6.90 (m, 2H); 5.90 (s, 2H); 4.82 (d, 1H); 4.01 (m, 1H); 2.92 (m, 2H);2.78 (m, 1H); 2.62 (m, 1H); 1.93 (m, 1H); 1.79 (m, 1H).

EXAMPLE 16 Compound 16N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-methylphenyl)-methyl]-1H-indole-2-carboxamide16.1 Ethyl5-trifluoromethyl-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylate

This compound was prepared by reacting 333 mg (1.295 mmol) of ethyl5-trifluoromethyl-1H-indole-2-carboxylate with 0.31 mL (2.59 mmol) of3-methylphenylmethanol in the presence of 0.92 g (3.826 mmol) of(cyanomethylene)tributylphosphorane (CMBP). The reaction mixture isstirred at 110° C. for 15 hours and then concentrated to dryness. Thecrude reaction product is then purified by flash chromatography on acolumn of silica gel in a mixture of heptane and ethyl acetate, to give376 mg of the expected product in the form of an oil.

¹H NMR (DMSO D₆), δ (ppm): 8.18 (s, 1H); 7.81-7.78 (m, 1H); 7.61-7.57(m, 1H), 7.53 (s, 1H); 7.14-7.12 (m, 2H); 7.01-6.91 (m, 1H); 6.75-6.73(m, 1H); 5.88 (s, 2H); 4.31 (q, 2H); 2.21 (s, 3H); 1.30 (t, 3H).

LC-MS: 362 ([M+H]⁺)

16.2N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-methyl-phenyl)methyl]-1H-indole-2-carboxamide(Compound 16)

To a solution of 150 mg (0.415 mmol) of ethyl5-trifluoromethyl-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylateprepared according to the protocol described in the preceding step and132 mg (0.498 mmol) of (6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl2,2-dimethylpropanoate, obtained in step 4.2, in 1.5 mL of dry toluene,maintained under an inert atmosphere, is added dropwise, at 0° C., 0.31mL (0.623 mmol) of a trimethylaluminium solution (2M/toluene). Thereaction mixture is stirred at 110° C. for 15 hours and thenconcentrated to dryness. The crude reaction product is then diluted withnormal hydrochloric acid solution. The product is extracted with ethylacetate and then purified by chromatography on a column of silica,eluting with a mixture of heptane and ethyl acetate, to give 82 mg ofthe expected product.

m.p.: 315-316° C.

¹H NMR (DMSO D₆), δ (ppm): 10.97 (s, 1H); 8.92 (d, 1H); 8.70 (d, 1H);8.22 (s, 1H); 7.81 (d, 1H); 7.62 (s, 1H); 7.60 (d, 1H); 7.14 (t, 1H);7.03-6.97 (m, 2H); 6.87-6.84 (m, 1H), 6.38 (t, 1H); 5.91 (s, 2H); 4.87(d, 2H); 2.19 (s, 3H).

EXAMPLE 17 Compound 17N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trifluoromethyl-1-[(3-methylphenyl)-methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

m.p.: 221-222° C.

¹H NMR (DMSO D₆), δ (ppm): 11.0 (s, 1H); 8.95 (s, 1H); 8.7 (s, 1H); 8.1(s, 1H); 8.0 (d, 1H); 7.6 (s, 1H); 7.5 (d, 1H); 7.15 (t, 1H); 7.05 (m,1H); 6.95 (s, 1H); 6.85 (m, 1H); 6.35 (t, 1H); 5.95 (s, 2H); 4.9 (d,2H); 2.2 (s, 3H).

EXAMPLE 18 Compound 18N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(3-methylphenyl)-methyl]-1H-indole-2-carboxamide18.1 1-Bromo-3-trimethylsilylbenzene

To a solution of 10 g (42.39 mmol) of 1,3-dibromobenzene in 80 mL ofanhydrous Et₂O, cooled to −78° C. and maintained under a nitrogenatmosphere, are added dropwise with stirring, over 30 minutes, 26.49 mL(42.39 mmol) of a solution of BuLi (1.5M/hexane). After stirring for afurther 30 minutes at −78° C., 5.96 mL (46.63 mmol) of TMSCI are addeddropwise to the reaction mixture. Stirring is maintained at thistemperature for 90 minutes and the reaction mixture is then hydrolysedby adding 15 mL of water. The product is extracted with ethyl acetate(3×50 mL). The combined organic phases are washed with saturated aqueousNaCl solution (2×25 mL), dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The crude reaction product is purified bychromatography on a column of silica gel, eluting with heptane, to give9.3 g of the expected 1-bromo-3-trimethylsilylbenzene, in the form of acolourless oil.

¹H NMR (DMSO D₆), δ (ppm): 5.75 (s, 1H), 7.46 (m, 1H), 7.4 (m, 1H), 7.22(t, 1H), 0.2 (s, 9H).

18.2 3-Trimethylsilylbenzaldehyde

To a solution of 5 g (21.89 mmol) of 1-bromo-3-trimethylsilylbenzeneprepared according to the protocol described in the preceding step, in40 mL of anhydrous Et₂O, cooled to 0° C. and maintained under a nitrogenatmosphere, are added dropwise, with stirring and over 30 minutes, 16.36mL (26.18 mmol) of BuLi (1.6M/hexane). Stirring is continued at 0° C.for a further 30 minutes, and the mixture is then maintained at roomtemperature for 90 minutes. 2.69 mL (34.91 mmol) of DMF, diluted with 17mL of anhydrous Et₂O, are then introduced into the reaction mixture.After stirring for 3 hours at room temperature, the reaction mixture ishydrolysed at 0° C. by successive addition of 10 mL of concentrated HClsolution and 100 mL of water. The product is extracted with 3×50 mL ofCH₂Cl₂. The combined organic phases are washed with 100 mL of water,dried over Na₂SO₄, filtered and evaporated under reduced pressure. Thecrude reaction product is purified by flash chromatography on a columnof silica gel, eluting with a gradient of from 10 to 20% of CH₂Cl₂ inheptane to give 1.82 g of the expected 3-trimethylsilylbenzaldehyde inthe form of a yellow oil.

¹H NMR (DMSO D₆), δ (ppm): 10.01 (s, 1H); 8.0 (s, 1H); 7.85 (d, 1H); 7.8(d, 1H); 7.5 (dd, 1H) 0.3 (s, 9H)

18.3 Ethyl 2-azido-3-(3-trimethylsilylphenyl)propenoate

To a solution of 2 g (87.5 mmol) of sodium in 30 mL of anhydrous EtOH,maintained under a nitrogen atmosphere and cooled to −10° C., is added,dropwise, a mixture of 31.4 mL (87.5 mmol) of ethyl azidoacetate (at 34%in CH₂Cl₂) and 3.9 g (21.87 mmol) of 3-trimethylsilylbenzaldehydeprepared according to the procedure described in the preceding step,diluted with 3 mL of EtOH. The reaction mixture is stirred at 0° C. for4 hours. It is then hydrolysed by adding, with vigorous stirring, 100 mLof aqueous NH₄Cl solution (30%). The aqueous phase is extracted with3×50 mL of EtOAc. The combined organic phases are washed with water,dried over Na₂SO₄ and concentrated under reduced pressure. The crudereaction product is purified by chromatography on a column of silicagel, eluting with an isocratic mixture of heptane and CH₂Cl₂ (80/20).1.7 g of the expected ethyl 2-azido-3-(3-trimethylsilylphenyl)propenoateare thus isolated in the form of a yellow oil.

¹H NMR (DMSO D₆), δ (ppm): 7.9 (d, 1H); 7.8 (s, 1H); 7.4 (d, 1H); 7.3(dd, 1H); 6.9 (s, 1H); 4.2 (q, 2H); 1.2 (t, 3H); 0.15 (s, 9H)

MS: [MH]⁺=289

18.4 Ethyl 5-trimethylsilyl-1H-indole-2-carboxylate

To a solution of 1.7 g (5.90 mmol) of ethyl2-azido-3-(3-trimethylsilylphenyl)propenoate prepared according to theprocedure described in the preceding step, in 25 mL of dry toluene,maintained under an inert atmosphere, is added 0.62 g (0.59 mmol) ofdirhodium (II) heptafluorobutyrate dimer complex. The reaction mixtureis stirred for 7 hours at 40° C. A second portion of 0.62 g (0.59 mmol)of dirhodium (II) heptafluorobutyrate dimer complex is added to thereaction mixture while maintaining the stirring and heating at 40° C.for a further 1 hour. After cooling to room temperature, the reactionmixture is filtered through silica gel, eluting with toluene. Thefiltrate is then concentrated under reduced pressure. The greenish solidobtained is triturated several times in a minimum amount of heptane,until a white powder is obtained. This powder is dried under reducedpressure to give 0.87 g of the expected ethyl5-trimethylsilyl-1H-indole-2-carboxylate in the form of a white powder.

m.p.=114-115° C.

¹H NMR (DMSO D₆), δ (ppm): 7.7 (s, 1H); 7.35 (d, 1H); 7.25 (d, 1H); 7.0(s, 1H); 4.2 (q, 2H); 1.2 (t, 3H); 0.15 (s, 9H)

LC-MS: [MH]⁻=260

18.5 Ethyl5-trimethylsilyl-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylate(Compound IIa)

The product is prepared according to a process similar to that describedin Example 16.1

¹H NMR (DMSO D₆), δ (ppm): 7.87 (s, 1H); 7.55 (d, 1H); 7.43 (d, 1H);7.36 (s, 1H); 7.13 (t, 1H); 7.01 (d, 1H); 6.91 (s, 1H); 6.73 (d, 1H);5.80 (s, 2H); 4.29 (q, 2H); 2.21 (s, 3H); 1.29 (t, 3H); 0.26 (s, 9H).

18.6N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(3-methyl-phenyl)methyl]-1H-indole-2-carboxamide(Compound 18)

The product is prepared according to a process similar to that describedin Example 16.2, starting with ethyl5-trimethylsilyl-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylate(Compound IIa).

m.p.: 154-155° C.

¹H NMR (DMSO D₆), δ (ppm): 10.8 (s, 1H); 8.95 (s, 1H); 8.7 (s, 1H); 7.9(s, 1H); 7.6 (d, 1H); 7.45 (s, 1H); 7.4 (d, 1H); 7.15 (t, 1H); 7.0 (m,2H); 6.85 (d, 1H); 6.35 (t, 1H); 5.9 (s, 2H); 4.9 (d, 2H); 2.2 (s, 3H);0.3 (s, 9H).

EXAMPLE 19 Compound 19N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

m.p.: 257-258° C.

¹H NMR (DMSO D₆), δ (ppm): 10.8 (s, 1H); 8.95 (s, 1H); 8.7 (s, 1H); 7.8(m, 1H); 7.55 (s, 1H); 7.45 (d, 1H); 7.15 (t, 1H); 7.05 (m, 2H); 6.95(s, 1H); 6.85 (m, 1H); 6.35 (t, 1H); 5.9 (s, 2H); 4.9 (d, 2H); 2.2 (s,3H).

EXAMPLE 20 Compound 20N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide20.1 2-(Chloromethyl)thiazole

To a solution of 0.5 g (4.34 mmol) of thiazol-2-ylmethanol in 5 mL ofcarbon tetrachloride and 6 mL of benzene are added 1.71 g (6.51 mmol) oftriphenylphosphine. The reaction mixture is stirred at 95° C. for 2hours. After cooling to room temperature, the reaction mixture isdiluted with dichloromethane and then filtered through Celite. Thefiltrate is concentrated under reduced pressure and the residue obtainedis purified by flash chromatography on a column of silica gel, elutingwith a mixture of hexane and ethyl acetate, to give 0.4 g of theexpected 2-(chloromethyl)thiazole in the form of a pale yellow oil.

¹H NMR (DMSO D₆), δ (ppm): 7.83-7.80 (m, 2H); 5.11 (s, 2H).

20.2 Ethyl5-trifluoromethyl-1-[(thiazol-2-yl)]methyl-1H-indole-2-carboxylate

To a suspension of 87 mg (1.983 mmol) of sodium hydride (55%) in 10 mLof dry DMF, maintained under an inert atmosphere, are added dropwise, atroom temperature, 340 mg (1.322 mmol) of ethyl5-trifluoromethyl-1H-indole-2-carboxylate in 5 mL of dry DMF. Thereaction mixture is stirred at 50° C. for 1 hour. A solution of 265 mg(1.983 mmol) of 2-(chloromethyl)thiazole, prepared according to theprotocol described in the preceding step, in 10 mL of THF is then addeddropwise, at 0° C. The reaction mixture is then stirred for 20 hours atroom temperature, and then diluted with 100 mL of ethyl acetate. Theaqueous phase is extracted with 30 mL of ethyl acetate. The combinedorganic phases are washed successively with saturated aqueous sodiumhydrogen carbonate solution, with water, with saturated aqueous sodiumchloride solution and then dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting oil is purified bychromatography on a column of silica, eluting with a mixture of heptaneand ethyl acetate. 265 mg of the expected product are isolated in theform of a colourless oil.

¹H NMR (DMSO D₆), δ (ppm): 8.18 (s, 1H); 7.95 (d, 1H); 7.72 (d, 1H);7.65 (d, 1H); 7.62 (d, 1H); 7.54 (s, 1H); 6.20 (s, 2H); 4.34 (q, 2H);1.31 (t, 3H).

LC-MS: 355 ([M+H]⁺

20.3N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)-methyl]-1H-indole-2-carboxamide(Compound 20)

This compound was prepared according to a process similar to thatdescribed in step 16.2, by reacting 125 mg (0.353 mmol) of ethyl5-trifluoromethyl-1-[(thiazol-2-yl)]methyl]-1H-indole-2-carboxylate,prepared according to the protocol described in the preceding step, with94 mg (0.353 mmol) of (6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl2,2-dimethylpropanoate, obtained in step 4.2, in the presence of 0.26 mL(0.529 mmol) of a solution of trimethylaluminium (2M/toluene). The crudereaction product is then purified by flash chromatography on a column ofsilica gel, in a mixture of dichloromethane and methanol, and thenwashed with a mixture (1/1) of ether and dichloromethane, to give 64 mgof the expected product.

m.p.: 282-283° C.

¹H NMR (DMSO D₆), δ (ppm): 10.99 (s, 1H); 8.94 (d, 1H); 8.72 (d, 1H);8.23 (s, 1H), 7.95 (d, 1H); 7.72-7.61 (m, 4H); 6.38 (t, 1H); 6.24 (s,2H); 4.88 (d, 2H).

LC-MS: 490 ([M+H]⁺

EXAMPLE 21 Compound 21N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 20.

m.p.: 243-244° C.

¹H NMR (DMSO D₆), δ (ppm): 11.0 (s, 1H); 8.95 (d, 1H); 8.7 (d, 1H); 8.2(s, 1H); 8.0 (d, 1H); 7.75 (d, 1H); 7.6 (m, 2H); 7.5 (d, 1H); 6.35 (t,1H); 6.25 (s, 2H); 4.9 (d, 2H).

EXAMPLE 22 Compound 22N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide22.1 Ethyl5-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxylate(Compound IIb)

This compound is prepared according to a process similar to thatdescribed in step 20.2, starting with ethyl5-trimethylsilyl-1H-indole-2-carboxylate described in step 18.4.

¹H NMR (DMSO D₆), δ (ppm): 7.80 (s, 1H); 7.64 (d, 1H); 7.61 (d, 1H);7.51 (d, 1H); 7.40 (d, 1H); 7.30 (s, 1H); 6.04 (s, 2H) 4.24 (q, 2H);1.23 (t, 3H); 0.19 (s, 9H).

22.6N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(thiazol-2-yl)-methyl]-1H-indole-2-carboxamide(Compound 22)

This compound is prepared according to a process similar to thatdescribed in step 16.2, starting with ethyl5-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxylatedescribed in the preceding step.

m.p.: 270-271° C.

¹H NMR (DMSO D₆), δ (ppm): 10.8 (s, 1H); 8.95 (d, 1H); 8.7 (d, 1H); 7.9(s, 1H); 7.7 (m, 2H); 7.55 (d, 1H); 7.5 (s, 1H); 7.45 (d, 1H); 6.35 (t,1H); 6.2 (s, 2H); 4.9 (d, 2H); 0.3 (s, 9H).

EXAMPLE 23 Compound 23N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 20.

m.p.: 151-153° C.

¹H NMR (DMSO D₆), δ (ppm): 10.8 (s, 1H); 8.95 (d, 1H); 8.7 (d, 1H); 7.8(m, 1H); 7.7 (d, 1H); 7.6 (m, 3H); 7.1 (m, 1H); 6.35 (t, 1H); 6.2 (s,2H); 4.9 (d, 2H).

EXAMPLE 24 Compound 24N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

The product is prepared according to a process similar to that describedin Example 20.

m.p.: 207-208° C.

¹H NMR (DMSO D₆), δ (ppm): 11.1 (s, 1H); 8.95 (d, 1H); 8.85 (s, 1H); 8.8(s, 1H); 8.7 (s, 1H); 7.7 (s, 1H); 7.65 (d, 1H); 7.58 (d, 1H); 6.35 (t,1H); 6.3 (s, 2H); 4.9 (d, 2H).

EXAMPLE 25 Compound 25N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxamide25.1 Ethyl 2-azido-3-(4-trimethylsilylphenyl)propenoate

1.26 g (54.96 mmol) of sodium and 30 mL of anhydrous ethanol areintroduced into a 100 mL round-bottomed flask, equipped with a magneticstirrer and maintained under a nitrogen atmosphere. The reaction mixtureis stirred at room temperature until a homogeneous solution is obtained.To this solution, cooled to −10° C., is added dropwise a solutioncontaining 16.83 mL (54.96 mmol) of ethyl azidoacetate (34% in CH₂Cl₂)and 5 g (27.48 mmol) of 4-trimethylsilylbenzaldehyde in 5 mL of ethanol.The reaction mixture is then stirred at 0° C. for 4 hours. The reactionmedium is hydrolysed by adding, with vigorous stirring, 100 mL ofammonium chloride solution (30% aqueous). The product is extracted withthree times 50 mL of ethyl acetate. The combined organic phases arewashed with twice 20 mL of water, dried over sodium sulfate andconcentrated under reduced pressure. The resulting oil is purified bychromatography on a column of silica gel, eluting with a mixture ofheptane and dichloromethane. 4.96 g of the expected product are isolatedin the form of a yellow oil.

¹H NMR (DMSO D₆), δ (ppm): 7.6 (d, 2H); 7.35 (d, 2H); 6.7 (s, 1H); 4.1(q, 2H); 1.1 (t, 3H); 0 (s, 9H).

25.2 Ethyl 6-trimethylsilyl-1H-indole-2-carboxylate

To a solution of 1.0 g (3.14 mmol) of ethyl2-azido-3-(4-trimethylsilylphenyl)propenoate obtained in the precedingstep, in 20 mL of dry toluene, maintained under an inert atmosphere, isadded 0.17 g (0.16 mmol) of dirhodium (II) heptafluorobutyrate dimercomplex. The reaction mixture is then stirred for 12 hours at 70° C.After cooling to room temperature, the reaction mixture is filteredthrough silica gel, eluting with ethyl acetate. The filtrate is thenconcentrated under reduced pressure. The residue is purified bychromatography on a column of silica gel, eluting with a mixture ofheptane and dichloromethane. 0.61 g of the expected product is isolatedin the form of a beige-coloured powder.

m.p.=127-129° C.

¹H NMR (DMSO D₆), δ (ppm): 11.7 (s, 1H); 7.41 (dd, 1H); 7.39 (d, 1H);6.97 (dd, 1H); 6.88 (d, 1H); 4.1 (q, 2H); 1.1 (t, 3H); 0.0 (s, 9H).

25.3 Ethyl6-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1H-indole-2-carboxylate(Compound IIc)

This compound was prepared according to a process similar to thatdescribed in step 20.2, by reacting 570 mg (2.18 mmol) of ethyl6-trimethylsilyl-1H-indole-2-carboxylate with 440 mg (3.27 mmol) of2-(chloromethyl)thiazole in the presence of 0.14 g (3.27 mmol) of sodiumhydride (55%). The crude reaction product is then purified by flashchromatography on a column of silica gel in a mixture of heptane andethyl acetate, to give 520 mg of the expected product.

¹H NMR (DMSO D₆), δ (ppm): 7.76 (s, 1H); 7.65-7.61 (m, 2H); 7.52 (d,1H); 7.28 (s, 1H); 7.22 (d, 1H); 6.09 (s, 2H); 4.23 (q, 2H); 1.22 (t,3H); 0.2 (s, 9H).

LC-MS: 359 ([M+H]⁺

25.4N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(thiazol-2-yl)-methyl]-1H-indole-2-carboxamide(Compound 25)

This compound was prepared according to a process similar to thatdescribed in step 16.2, by reacting 200 mg (0.523 mmol) of ethyl6-trimethylsilyl-1-[(thiazol-2-yl)]methyl-1H-indole-2-carboxylate,prepared in the preceding step, with 178 mg (0.670 mmol) of(6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate,obtained in step 4.2, in the presence of 0.39 mL (0.784 mmol) of asolution of trimethylaluminium (2M/toluene). The product was isolated bypurification by chromatography on a column of silica, eluting with amixture of dichloromethane and ethanol. 120 mg of the expected productare obtained.

m.p.: 219-220° C.

¹H NMR (DMSO D₆), δ (ppm): 10.76 (s, 1H); 8.86 (d, 1H); 8.64 (d, 1H);7.76 (s, 1H); 7.67 (d, 1H); 7.63 (d, 1H); 7.50 (d, 1H); 7.42 (s, 1H);7.22 (d, 1H); 6.29 (t, 1H); 6.14 (s, 2H); 4.79 (d, 2H); 0.19 (s, 9H).

LC-MS: 494 ([M+H]⁺

EXAMPLE 26 Compound 26N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

m.p.: 237-238° C.

¹H NMR (DMSO D₆), δ (ppm): 8.9 (s, 1H); 8.7 (s, 1H); 8.5 (d, 2H); 8.3(s, 1H); 7.8 (d, 1H); 7.75 (s, 1H); 7.6 (d, 1H); 7.0 (m, 2H); 6.35 (t,1H); 6.0 (s, 2H); 4.9 (d, 2H).

EXAMPLE 27 Compound 27N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trifluoromethyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

MP: 261-263° C.

¹H NMR (DMSO D₆), δ (ppm): 8.9 (s, 1H); 8.7 (s, 1H); 8.5 (d, 2H); 8.1(m, 2H); 7.7 (s, 1H); 7.5 (d, 1H); 6.95 (d, 2H); 6.35 (t, 1H); 6.0 (s,2H); 4.9 (d, 2H).

EXAMPLE 28 Compound 28N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide28.1 Ethyl5-trimethylsilyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxylate(Compound IId)

The product is prepared according to a process similar to that describedin Example 16.1, starting with ethyl5-trimethylsilyl-1H-indole-2-carboxylate prepared in step 18.4.

¹H NMR (DMSO D₆), δ (ppm): 8.37 (d, 2H), 7.83 (s, 1H), 7.47 (d, 1H),7.37 (d, 1H), 7.34 (s, 1H), 6.84 (d, 2H), 5.80 (s, 2H), 4.18 (q, 2H),1.18 (t, 3H), 0.19 (s, 9H).

28.2N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[(pyrid-4-yl)-methyl]-1H-indole-2-carboxamide(Compound 28)

The product is prepared according to a process similar to that describedin Example 16.2, starting with ethyl5-trimethylsilyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxylate preparedin the preceding step.

m.p.: 208-210° C.

¹H NMR (DMSO D₆), δ (ppm): 8.9 (s, 1H); 8.7 (s, 1H); 8.45 (d, 2H); 7.95(s, 1H); 7.58 (s, 1H); 7.5 (d, 1H); 7.4 (d, 1H); 7.0 (d, 2H); 6.35 (t,1H); 5.9 (s, 2H); 4.9 (d, 2H); 0.3 (s, 9H).

EXAMPLE 29 Compound 29N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

m.p.: 290-291° C.

¹H NMR (DMSO D₆), δ (ppm): 8.9 (s, 1H); 8.7 (s, 1H); 8.45 (d, 2H); 7.8(m, 1H); 7.6 (s, 1H); 7.5 (dd, 1H); 7.1 (m, 1H); 7.0 (d, 2H); 6.35 (t,1H); 5.9 (s, 2H); 4.9 (d, 2H).

EXAMPLE 30 Compound 30N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide30.1 Ethyl5-trifluoromethyl-1-[(4-pyridyl)methyl)]-1H-pyrrolo[2,3-b]pyrid-2-carboxylate

This compound was prepared according to a process similar to thatdescribed in step 16.1, by reacting 480 mg (1.859 mmol) of ethyl5-trifluoromethyl-1H-pyrrolo[2,3-b]pyrid-2-carboxylate with 406 mg(3.718 mmol) of 4-pyridylmethanol in the presence of 0.89 g (3.718 mmol)of cyanomethylenetributylphosphorane (CMBP). The crude reaction productis then purified by flash chromatography on a column of silica gel in amixture of heptane and ethyl acetate, to give 582 mg of the expectedproduct in the form of a white solid.

¹H NMR (DMSO D₆), δ (ppm): 8.84 (s, 1H); 8.72 (s, 1H); 8.45 (d, 2H);7.56 (s, 1H); 6.98 (d, 2H); 5.94 (s, 2H); 4.29 (q, 2H); 1.25 (t, 3H).

LC-MS: 350 ([M+H]⁺

30.2N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)-methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(Compound 30)

This compound was prepared according to a process similar to thatdescribed in step 16.2, by reacting 200 mg (0.573 mmol) of ethyl5-trifluoromethyl-1-[(4-pyridyl)methyl)]-1H-pyrrolo[2,3-b]pyrid-2-carboxylate,prepared according to the protocol described in the preceding step, with182 mg (0.687 mmol) of (6-amino-thiazolo[5,4-b]pyrid-2-yl)-methyl2,2-dimethylpropanoate, obtained in step 4.2, in the presence of 0.43 mL0.859 mmol) of a solution of trimethylaluminium (2M/toluene). The crudereaction product is then purified by chromatography on a column ofsilica, eluting with a mixture of dichloromethane and methanol, to give71 mg of the expected product.

m.p.: 275-276° C.

¹H NMR (DMSO D₆), δ (ppm): 11.03 (s, 1H); 8.89 (d, 1H); 8.82 (s, 2H);8.65 (d, 1H); 8.45 (d, 2H); 7.74 (s, 1H); 7.04 (d, 2H); 6.38 (t, 1H);5.99 (s, 2H); 4.87 (d, 2H).

LC-MS: 485 ([M+H]⁺

EXAMPLE 31 Compound 31N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide31.1 Ethyl6-trimethylsilyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxylate(Compound IIe)

The product is prepared according to a process similar to that describedin Example 16.1, starting with ethyl6-trimethylsilyl-1H-indole-2-carboxylate prepared in step 25.2.

¹H NMR (DMSO D₆), δ (ppm): 8.2 (d, 2H); 7.49 (d, 1H); 7.42 (s, 1H); 7.15(s, 1H); 7.05 (d, 1H); 6.70 (d, 2H); 5.68 (s, 2H); 4.01 (q, 2H); 1.01(t, 3H); 0.0 (s, 9H).

31.2N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(pyrid-4-yl)-methyl]-1H-indole-2-carboxamide(Compound 31)

The product is prepared according to a process similar to that describedin Example 16.2, starting with ethyl6-trimethylsilyl-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxylate preparedin the preceding step.

m.p.: 213-214° C.

¹H NMR (DMSO D₆), δ (ppm): 8.9 (s, 1H); 8.7 (s, 1H); 8.45 (d, 2H); 7.8(d, 1H); 7.65 (s, 1H); 7.55 (s, 1H); 7.35 (d, 1H); 7.05 (d, 2H); 6.35(t, 1H); 6.0 (s, 2H); 4.9 (d, 2H); 0.25 (s, 9H).

EXAMPLE 32 Compound 32N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[[(3-trifluoromethyl)-phenyl]methyl]-1H-indole-2-carboxamide32.1 Ethyl 5-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]methyl]-1H-indole-2-carboxylate(Compound IIf)

The compound was prepared according to a process similar to thatdescribed in step 16.1, by reacting 0.49 g (1.87 mmol) of ethyl5-trimethylsilyl-1H-indole-2-carboxylate, prepared in step 18.4, with0.51 mL (3.749 mmol) of 3-(trifluoromethyl)phenylmethanol in thepresence of 0.9 g (3.749 mmol) of cyanomethylenetributylphosphorane(CMBP). The crude reaction product is then purified by chromatography ona column of silica in a mixture of heptane and ethyl acetate, to give730 mg of the expected product.

¹H NMR (DMSO D₆), δ (ppm): 7.90 (s, 1H); 7.62-7.57 (m, 2H); 7.51-7.43(m, 3H); 7.40 (s, 1H); 7.17 (d, 1H); 5.92 (s, 2H); 4.28 (q, 2H); 1.26(t, 3H); 0.27 (s, 9H).

LC-MS: 420 ([M+H]⁺

32.2N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trimethylsilyl-1-[[(3-trifluoro-methyl)phenyl]methyl]-1H-indole-2-carboxamide

This compound was prepared according to a process similar to thatdescribed in step 16.2, by reacting 200 mg (0.477 mmol) of ethyl5-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]methyl]-1H-indole-2-carboxylate,prepared in the preceding step, with 152 mg (0.572 mmol) of(6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate,obtained in step 4.2, in the presence of 0.36 mL (0.715 mmol) of asolution of trimethylaluminium (2M/toluene). The product is isolated bypurification by flash chromatography on a column of silica gel in amixture of heptane and ethyl acetate. 128 mg of the expected product areobtained.

m.p.: 152-153° C.

¹H NMR (DMSO D₆), δ (ppm): 10.82 (s, 1H); 8.91 (d, 1H); 8.68 (d, 1H);7.92 (s, 1H); 7.61-7.42 (m, 6H); 7.31 (d, 1H); 6.37 (t, 1H); 5.97 (s,2H); 4.87 (d, 2H); 0.28 (s, 9H).

LC-MS: 555 ([M+H]⁺

EXAMPLE 33 Compound 33N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[[(3-trifluoromethyl)phenyl]-methyl]-1H-indole-2-carboxamide33.1 Methyl6-fluoro-1-[(3-trifluoromethylphenyl)methyl]-1H-indole-2-carboxylate

This compound was prepared according to a process similar to thatdescribed in step 16.1, by reacting 475 mg (2.459 mmol) of methyl6-fluoro-1H-indole-2-carboxylate with 0.67 mL (4.918 mmol) of3-trifluoromethylphenylmethanol in the presence of 1.18 g (4.918 mmol)of cyanomethylenetributylphosphorane (CMBP). The crude reaction productis then purified by chromatography on a column of silica in a mixture ofheptane and ethyl acetate, to give 706 mg of the expected product in theform of a white solid.

¹H NMR (DMSO D₆), δ (ppm): 7.78 (dd, 1H); 7.61-7.49 (m, 4H); 7.43 (s,1H); 7.19 (d, 1H); 7.05 (dt, 1H); 5.91 (s, 2H); 3.80 (s, 3H).

LC-MS: 351 ([M+H]⁺

33.2N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-fluoro-1-[[(3-trifluoromethyl)-phenyl]methyl]-1H-indole-2-carboxamide(Compound 33)

This compound was prepared according to a process similar to thatdescribed in step 16.2, by reacting 200 mg (0.569 mmol) of methyl6-fluoro-1-[(3-trifluoromethylphenyl)methyl]-1H-indole-2-carboxylate,prepared according to the protocol described in the preceding step, with181 mg (0.683 mmol) of (6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl2,2-dimethylpropanoate, obtained in step 4.2, in the presence of 0.43 mL(0.853 mmol) of a solution of trimethylaluminium (2M/toluene). The crudereaction product is then purified by chromatography on a column ofsilica gel in a mixture of dichloromethane and methanol, to give 89 mgof the expected product.

m.p.: 217-218° C.

¹H NMR (DMSO D₆), δ (ppm): 10.81 (s, 1H); 8.89 (d, 1H); 8.67 (d, 1H);7.82 (dd, 1H); 7.60-7.49 (m, 5H); 7.33 (d, 1H); 7.06 (dt, 1H); 6.37 (t,1H); 5.95 (s, 2H); 4.87 (d, 2H).

LC-MS: 501 ([M+H]⁺

EXAMPLE 34 Compound 34N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[[(3-trifluoromethyl)-phenyl]methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

m.p.: 312-314° C.

¹H NMR (DMSO D₆), δ (ppm): 11.0 (s, 1H); 8.90 (s, 1H); 8.85 (s, 1H); 8.8(s, 1H); 8.65 (s, 1H); 7.7 (s, 1H); 7.6 (m, 2H); 7.5 (m, 1H); 7.35 (m,1H); 6.35 (t, 1H); 6.05 (s, 2H); 4.9 (d, 2H).

EXAMPLE 35 Compound 35N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[[(3-trifluoromethyl)-phenyl]methyl]-1H-indole-2-carboxamide35.1 Ethyl6-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]methyl]-1H-indole-2-carboxylate(Compound IIg)

The product is prepared according to a protocol similar to thatdescribed in Example 32.1, starting with ethyl6-trimethylsilyl-1H-indole-2-carboxylate described in Example 25.

¹H NMR (DMSO D₆), δ (ppm): 7.49-7.45 (m, 2H); 7.36-7.33 (m, 2H); 7.25(t, 1H); 7.12 (s, 1H); 7.04-7.00 (m, 2H); 5.73 (s, 2H); 4.04 (q, 2H);1.03 (t, 3H); 0.00 (s, 9H).

35.2N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[[(3-trifluoro-methyl)phenyl]methyl]-1H-indole-2-carboxamide(Compound 35)

The product is prepared according to a process similar to that describedin Example 32.2, starting with ethyl6-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]methyl]-1H-indole-2-carboxylateprepared in the preceding step.

m.p.: 180-181° C.

¹H NMR (DMSO D₆), δ (ppm): 10.85 (s, 1H); 8.95 (s, 1H); 8.75 (s, 1H);7.75 (m, 2H); 7.65 (s, 1H); 7.6-7.4 (m, 4H); 7.3 (d, 1H); 6.35 (t, 1H);6.0 (s, 2H); 4.9 (d, 2H); 0.25 (s, 9H).

EXAMPLE 36 Compound 36N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-methylphenyl)-methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

m.p.: 335-336° C.

¹H NMR (DMSO D₆), δ (ppm): 11.0 (s, 1H); 8.9 (s, 1H); 8.85 (s, 1H); 8.75(s, 1H); 8.65 (s, 1H); 7.6 (s, 1H); 7.1 (m, 1H); 7.0 (m, 2H); 6.9 (m,1H); 6.3 (t, 1H); 5.95 (s, 2H); 4.9 (d, 2H); 2.15 (s, 3H).

EXAMPLE 37 Compound 37N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(3-methylphenyl)-methyl]-1H-indole-2-carboxamide37.1 Ethyl6-trimethylsilyl-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylate(Compound IIh)

The product is prepared according to a protocol similar to thatdescribed in Example 32.1, starting with ethyl6-trimethylsilyl-1H-indole-2-carboxylate described in Example 25.

¹H NMR (DMSO D₆), δ (ppm): 7.71-7.68 (m, 2H); 7.33 (s, 1H); 7.24-7.21(m, 1H); 7.14-7.11 (m, 2H); 7.09-7.0 (m, 1H); 6.81-6.79 (m, 1H); 5.85(s, 2H); 4.30 (q, 2H); 2.21 (s, 3H); 1.17 (t, 3H), 0.25 (s, 9H).

37.2N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trimethylsilyl-1-[(3-methyl-phenyl)methyl]-1H-indole-2-carboxamide(Compound 37)

The product is prepared according to a process similar to that describedin Example 32.2, starting with ethyl6-trimethylsilyl-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylateprepared in the preceding step.

m.p.: 168-169° C.

¹H NMR (DMSO D₆), δ (ppm): 10.8 (s, 1H); 8.9 (s, 1H); 8.7 (s, 1H); 7.7(m, 2H); 7.48 (s, 1H); 7.25 (d, 1H); 7.15 (m, 1H); 7.0 (m, 2H); 6.9 (m,1H); 6.35 (t, 1H); 5.9 (s, 2H); 4.9 (d, 2H); 2.2 (s, 3H); 0.3 (s, 9H).

EXAMPLE 38 Compound 38N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[[(3-trifluoromethyl)-phenyl]methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

m.p.: 237-239° C.

¹H NMR (DMSO D₆), δ (ppm): 11.0 (s, 1H); 8.95 (s, 1H); 8.7 (s, 1H); 8.25(s, 1H); 7.85 (d, 1H); 7.7 (s, 1H); 7.65-7.5 (m, 4H); 7.35 (m, 1H); 6.35(t, 1H); 6.0 (s, 2H); 4.9 (d, 2H).

EXAMPLE 39 Compound 39N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-6-trifluoromethyl-1-[[(3-trifluoromethyl)-phenyl]methyl]-1H-indole-2-carboxamide

The product is prepared according to a process similar to that describedin Example 16.

m.p.: 197-198° C.

¹H NMR (DMSO D₆), δ (ppm): 11.0 (s, 1H); 8.95 (s, 1H); 8.7 (s, 1H); 8.15(s, 1H); 8.05 (d, 1H); 7.65-7.45 (m, 5H); 7.35 (m, 1H); 6.35 (t, 1H);6.1 (s, 2H); 4.9 (d, 2H).

Table I that follows illustrates the chemical structures and thephysical properties of a number of examples of compounds according tothe invention.

In this table:

-   -   the column “m.p. (° C.)” indicates the melting points of the        products in degrees Celsius (° C.);    -   W represents an oxygen atom;    -   n is equal to 1;    -   all the compounds are in the form of the free base;    -   Me corresponds to a methyl group;    -   tBu corresponds to a tert-butyl group.

TABLE 1 (I)

No. X₁, X₂, X₃, X₄ Y A m.p. (° C.) 1 CH, C—F, CH, CH

274-275 2 CH, C—F, CH, CH

264-265 3 CH, C—F, CH, CH

250-251 4 CH, C—F, CH, CH

225-226 5 CH, C—F, CH, CH

244-246 6 CH, C—F, CH, CH

231-232 7 CH, C—F, CH, CH

235-236 8 CH, C—CF₃, CH, N

274-275 9 CH, C—F, CH, CH

265-266 10 CH, C—F, CH, CH

214-215 11 CH, C—F, CH, CH

299-300 12 CH, C—F, CH, CH

248-250 13 CH, C—F, CH, CH

224-225 14 CH, C—F, CH, CH

224-225 15 CH, C—F, CH, CH

204-206 16 CH, C—CF₃, CH, CH

315-316 17 CH, CH, C—CF₃, CH

221-222 18 CH, C—SiMe₃, CH, CH

154-155 19 CH, CH, C—F, CH

257-258 20 CH, C—CF₃, CH, CH

282-283 21 CH, CH, C—CF₃, CH

243-244 22 CH, C—SiMe₃, CH, CH

270-271 23 CH, CH, C—F, CH

151-153 24 CH, C—CF₃, CH, N

207-208 25 CH, CH, C—SiMe₃, CH

219-220 26 CH, C—CF₃, CH, CH

237-238 27 CH, CH, C—CF₃, CH

261-263 28 CH, C—SiMe₃, CH, CH

208-210 29 CH, CH, C—F, CH

290-291 30 CH, C—CF₃, CH, N

275-276 31 CH, CH, C—SiMe₃, CH

213-214 32 CH, C—SiMe₃, CH, CH

152-153 33 CH, CH, C—F, CH

217-218 34 CH, C—CF₃, CH, N

312-314 35 CH, CH, C—SiMe₃, CH

180-181 36 CH, C—CF₃, CH, N

335-336 37 CH, CH, C—SiMe₃, CH

168-169 38 CH, C—CF₃, CH, N

237-239 39 CH, CH, C—CF₃, CH

197-198

The compounds according to the invention underwent in vitro and in vivopharmacological tests that demonstrated their value as therapeuticallyactive substances. These compounds have antagonist or agonist activitytowards the TRPV1 (or VR1) receptors.

Test of Inhibition of the Current Induced with Capsaicin on Rat DRGs

-   -   Primary culture of rat dorsal root ganglion (DRG) cells:

DRG neurones naturally express the TRPV1 receptor.

The primary cultures of newborn rat DRGs are prepared using 1-day-oldrats. Briefly, after dissection, the ganglions are trypsinized and thecells dissociated by mechanical trituration. The cells are resuspendedin an Eagle basal culture medium containing 10% foetal calf serum, 25 mMKCl, 2 mM glutamine, 100 μg/ml gentamicin and 50 ng/ml of NGF, and thendeposited on glass slides coated with laminin (0.25×10⁶ cells perslide), which are then placed in Corning 12-well dishes. The cells areincubated at 37° C. in a humidified atmosphere containing 5% CO₂ and 95%air. Cytosine β-D-arabinoside (1 μM) is added 48 hours after culturing,to prevent the growth of non-neuronal cells. The slides are transferredinto experimental chambers for the patch-clamp studies after 7-10 daysof culturing.

Electrophysiology:

The measuring chambers (volume 800 μl) containing the cell preparationare placed on the platform of an inverted microscope (Olympus IMT2)equipped with Hoffman optics (Modulation Contrast, New York) andobserved at a magnification of 400×. The chambers are continuouslygravity-influxed (2.5 ml/min) using a solution distributor accepting 8inlets and whose sole outlet, consisting of a polyethylene tube(aperture 500 μm), is placed less than 3 mm from the cell under study.The “whole cell” configuration of the patch-clamp technique was used.The borosilicate-glass pipettes (resistance 5-10 MOhms) are brought tothe cell by means of a 3D piezoelectric micromanipulator (Burleigh,PC1000). The overall currents (membrane potential set at −60 mV) arerecorded with an Axopatch 1D amplifier (Axon Instruments, Foster City,Calif.), connected to a PC running the Pclamp8 software (AxonInstrument). The current plots are recorded on paper and simultaneouslydigitized (sampling frequency 15 to 25 Hz) and acquired on the harddrive of the PC.

The application of a 300 nM capsaicin solution induces on the DRG cells(voltage set at −70 mV) an entering cationic current. In order tominimize the desensitization of the receptors, a minimum interval of 1minute between two applications of capsaicin is observed. After acontrol period (stabilization of the capsaicin response alone), the testcompounds are applied alone at a given concentration (concentration of10 nM or 1 nM) for a time of 4 to 5 minutes, during which severalcapsaicin+compound tests are performed (to obtain the maximuminhibition). The results are expressed as a percentage of inhibition ofthe control capsaicin response.

In the case of the VR1 antagonist compounds, the percentages ofinhibition of the capsaicin response (1 μM) are between 20% and 100% forthe most active compounds of the invention tested at concentrations offrom 0.1 to 10 nM. They are therefore effective antagonists of receptorsof TRPV1 type. Table 2 gives an example of the percentage of inhibitionobtained with the compounds of the invention.

TABLE 2 Compound No. % inhibition in DRG patch 4 65.5% (0.1 nM) 11  62%(100 nM)Pain Induced by Intraplantar Administration of Capsaicin to Mice.

The intraplantar injection of capsaicin to mice rapidly producesshort-lived nociceptive behaviour, which is reflected by licking, bitingand flexing of the administered leg. These nociceptive responses areprobably associated with the activation of the local TRPV1 receptors bythe capsaicin.

Methodology:

(E)-Capsaicin is initially diluted to 3 mg/ml in DMSO, and then dilutedagain for its final use to 1.5 μg/20 μl in physiological saline. Theadministration of solvent has no effect on the behaviour of the mouse.The capsaicin is injected into the hind legs of the animal, on the upperface.

The test compounds are administered orally 120 minutes before theinjection of capsaicin. Two hours after administration of the compounds,the mice are placed in a glass beaker. The nociceptive behaviour of theanimals is then assessed immediately by the experimenter, and theduration of the capsaicin-induced behavioural manifestations is timedover a period of 2 minutes (licking and biting, total or partial flexureof the injected leg).

For each compound, an inhibition corresponding to the mean of thecapsaicin-induced nociceptive responses, in response to a dose of testproduct (expressed in mg/kg) administered orally to a sample of a givennumber (n) of mice, is determined.

Table 3 gives an example of a percentage of inhibition obtained with thecompounds of the invention.

TABLE 3 % inhibition of the capsaicin-induced Compound No. Dose nnociceptive responses 4 10 mg/kg 10 37% (±8%)

The compounds of the invention may thus be used for the preparation ofmedicaments, especially for the preparation of a medicament forpreventing or treating pathologies in which receptors of TRPV1 type areinvolved.

The compounds of the invention may be useful for preventing or treatingpathologies in which receptors of TRPV1 type are involved.

Thus, a subject of the invention is medicaments comprising at least onecompound of formula (I), or a pharmaceutically acceptable salt, oralternatively a hydrate or a solvate of the said compound.

These medicaments find their therapeutic use especially in theprevention and/or treatment of pain and inflammation, chronic pain,neuropathic pain (trauma-related, diabetic, metabolic, infection-relatedor toxic pain, or pain induced by an anticancer or iatrogenictreatment), (osteo)arthritic pain, rheumatic pain, fibromyalgia, backpain, cancer-related pain, facial neuralgia, headaches, migraine, dentalpain, burns, sunburn, animal bites or insect bites, post-herpeticneuralgia, muscular pain, trapped nerves (central and/or peripheral),spinal column and/or brain trauma, ischaemia (of the spinal columnand/or the brain), neurodegeneration, haemorrhagic strokes (of thespinal column and/or of the brain) and post-stroke pain.

The compounds of the invention may also be used for preventing and/ortreating metabolic disorders such as diabetes.

The compounds of the invention may be used for preventing and/ortreating urological disorders such as hyperactivity of the bladder,vesical hyperreflexia, vesical instability, incontinence, urgentmicturition, urinary incontinence, cystitis, nephritic colic, pelvichypersensitivity and pelvic pain.

The compounds of the invention may be useful for preventing and/ortreating gynaecological disorders, for instance vulvodynia and painassociated with salpingitis or with dysmenorrhoea.

These products may also be used for preventing and/or treatinggastrointestinal disorders such as gastro-oesophageal reflux disorder,stomach ulcers, duodenal ulcers, functional dyspepsia, colitis, IBS,Crohn's disease, pancreatitis, oesophagitis and biliary colic.

Similarly, the products of the present invention may be useful in theprevention and/or treatment of respiratory disorders such as asthma,coughing, chronic obstructive pulmonary disease (COPD),bronchoconstriction and inflammatory disorders of the respiratorysystem.

These products may also be used for preventing and/or treatingpsoriasis, pruritus, dermal, ocular or mucous irritation, herpes andzona.

The compounds of the invention may also be used for treating depression.

The compounds of the invention may also be used for treating centralnervous system diseases such as multiple sclerosis.

The compounds of the invention may also be used for treating cancers.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, at leastone compound according to the invention. These pharmaceuticalcompositions contain an effective dose of at least one compoundaccording to the invention or a pharmaceutically acceptable salt, ahydrate or a solvate of the said compound and also at least onepharmaceutically acceptable excipient.

The said excipients are chosen, according to the pharmaceutical form andthe desired mode of administration, from the usual excipients known tothose skilled in the art.

The pharmaceutical compositions of the present invention may beadministered via the oral, sublingual, subcutaneous, intramuscular,intravenous, topical, local, intratracheal, intranasal, transdermal orrectal route. These compositions may be administered in a unitadministration form, as a mixture with standard pharmaceuticalexcipients. They are intended to be administered to animals and humanbeings for the prophylaxis or treatment of the disorders or diseasesmentioned above.

The appropriate unit forms of administration include oral forms such astablets, soft or hard gel capsules, powders, granules and oral solutionsor suspensions, sublingual, buccal, intratracheal, intraocular andintranasal administration forms, forms for administration by inhalation,topical, transdermal, subcutaneous, intramuscular or intravenousadministration forms, rectal administration forms and implants. Fortopical application, the compounds according to the invention may beused in creams, gels, pomades or lotions.

By way of example, a unit form of administration of a compound accordingto the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium  6.0 mg Corn starch 15.0 mgHydroxypropylmethylcellulose 2.25 mg Magnesium stearate  3.0 mg

The said unit forms are dosed to allow a daily administration of from0.001 to 30 mg of active principle per kg of body weight, according tothe galenical form.

There may be particular cases in which higher or lower dosages areappropriate: such dosages do not depart from the scope of the invention.According to the usual practice, the dosage that is appropriate for eachpatient is determined by the doctor according to the mode ofadministration, the weight and the response of the said patient.

The compounds of the invention may also be used for the preparation ofmedicaments, especially for the preparation of a medicament forpreventing or treating pathologies in which receptors of TRPV1 type areinvolved, as mentioned previously.

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises the administration to a patient of an effective dose of acompound according to the invention, or a pharmaceutically acceptablesalt, or hydrate or solvate thereof.

What is claimed is:
 1. A compound corresponding to formula (I):

wherein: X₁, X₂, and X₃ represent, independently of each other, a groupC—R₁; and X₄ represents a nitrogen atom; W represents an oxygen orsulfur atom; n is equal to 0, 1, 2 or 3; Y represents an aryl or aheteroaryl optionally substituted with one or more groups chosen from ahalogen atom, a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, hydroxyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₄R₅, nitro, NR₄R₅, C₁-C₆-thioalkyl,thiol, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₄R₅, NR₆C(O)R₇,NR₆SO₂R₈, C(O)NR₄R₅, OC(O)NR₄R₅, —Si—(C₁-C₆-alkyl)₃, —SF₅,aryl-C₁-C₅-alkylene or aryl, heteroaryl-C₁-C₅-alkylene or heteroaryl;the groups C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O-being optionallysubstituted with a hydroxyl group, C₁-C₆-alkoxy or NR₄R₅, the aryl andheteroaryl groups being optionally substituted with one or moresubstituents R₉, which may be identical to or different from each other;A represents the group of formula:

Z₁, Z₂, Z₃ and Z₄ represent, independently of each other, a nitrogenatom, a carbon atom or a group C—R₂, at least one from among Z₁, Z₂, Z₃and Z₄ corresponding to a nitrogen atom and one from among Z₁, Z₂, Z₃and Z₄, corresponding to a carbon atom, being bonded to the nitrogenatom of the amide or of the thioamide of formula (I); Ra and Rb form,together with the carbon atoms that bear them, either a partiallyunsaturated cycloalkyl, or an aryl; or a heterocycle, or a heteroaryl,which is 5- to 7-membered, comprising from 1 to 3 heteroatoms chosenfrom O, S and N; wherein when Ra and Rb together form, with the carbonatoms that bear them, a 5-membered ring, this ring comprising a nitrogenatom and carbon atoms, this ring being partially saturated orunsaturated, is excluded; the partially unsaturated cycloalkyl, thearyl, the heterocycle or the heteroaryl are optionally substituted withone or more substituents R₃; R₁ is chosen from a hydrogen atom, ahalogen atom, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryloxy-C₁-C₆-alkyl,heteroaryloxy-C₁-C₆-alkyl, aryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl,heteroaryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl,heteroarylthio-C₁-C₆-alkyl, aryl-C₁-C₃-alkylene-thio-C₁-C₆-alkyl,heteroaryl-C₁-C₃-alkylene-thio-C₁-C₆-alkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₄R₅, nitro, NR₄R₅, C₁-C₆-thioalkyl,C₃-C₇-cycloalkylthio, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-thio,—S(O)—C₁-C₆-alkyl, —S(O)—C₃-C₇-cycloalkyl,—S(O)—C₁-C₃-alkylene-C₃-C₇-cycloalkyl, C₁-C₆-alkyl-S(O)₂—,C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, SO₂NR₄R₅, —Si—(C₁-C₆-alkyl)₃,—SF₅, NR₆C(O)R₇, NR₆SO₂R₈, C(O)NR₄R₅, OC(O)NR₄R₅, aryl, heteroaryl,aryl-C₁-C₅-alkylene, heteroaryl-C₁-C₅-alkylene, aryloxy, arylthio,heteroaryloxy or heteroarylthio; the heteroaryl or aryl groups beingoptionally substituted with one or more substituents R₉, which may beidentical to or different from each other; R₂ represents a hydrogenatom, a halogen atom or a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-O—, hydroxyl, thiolor C₁-C₆-fluoroalkoxy; R₃ represents, when it is borne by a carbon atom,a hydrogen atom or a hydroxyl, thiol, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-alkoxy-C₁-C₃-alkylene, C₃-C₇-cycloalkyloxy-C₁-C₃-alkylene,C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy-C₁-C₃-alkylene, C(O)NR₄R₅,C(O)O—C₁-C₆-alkyl, CO₂H, oxo or thio group; the groups C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-alkoxy-C₁-C₃-alkylene, C₃-C₇-cycloalkyloxy-C₁-C₃-alkylene,C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy-C₁-C₃-alkylene are optionallysubstituted with a hydroxyl group, C₁-C₆-alkoxy, —OC(O)—C₁-C₆-alkyl orNR₄R₅; or R₃ represents, when it is borne by a nitrogen atom, a hydrogenatom or a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C(O)—,C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—, C₁-C₆-fluoroalkyl-C(O)—,aryl-S(O), C₁-C₆-alkyl-S(O)—, C₁-C₆-fluoroalkyl-S(O)—, aryl-S(O)₂—,C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, C₁-C₆-alkyl-O—C(O)—,aryl-C₁-C₃-alkyl-O—C(O)—, C₃-C₇-cycloalkyl-O—C(O)—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-O—C(O)—, C₁-C₆-fluoroalkyl-O—C(O),aryl-O—C(O)—, heteroaryl-O—C(O)—, heteroaryl or aryl; the heteroaryl andaryl groups being optionally substituted with one or more substituentsR₉, which may be identical to or different from each other; the groupsC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene andC₁-C₆-fluoroalkyl are optionally substituted with a hydroxyl group,C₁-C₆-alkoxy or NR₄R₅; R₄ and R₅, represent, independently of eachother, a hydrogen atom or a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₅-alkylene or aryl, or R₄ andR₅ together form, with the nitrogen atom that bears them, an azetidine,pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazineor homopiperazine group; the group NR₄R₅ being optionally substitutedwith a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene, aryl, heteroaryl,aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂,C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—,aryl-C(O)—, C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—, C₁-C₆-fluoroalkyl-C(O)—,hydroxyl, C₁-C₆-alkyloxy, C₃-C₇-cycloalkyloxy,C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy, C₁-C₆-fluoroalkyl,aryloxy-C₁-C₆-alkylene, aryloxy, heteroaryloxy-C₁-C₆-alkylene orheteroaryloxy; R₆ and R₇ represent, independently of each other, ahydrogen atom or a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene or aryl; the arylgroup being optionally substituted with one or more substituents chosenfrom a halogen atom and a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-fluoroalkoxy, nitro or cyano; or R₆ and R₇ together form a 4- to7-membered lactam comprising the nitrogen atom and the C(O) group thatbear them; R₈ represents a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene or aryl; the arylgroup being optionally substituted with one or more substituents chosenfrom a halogen atom, a group C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,C₁-C₆-fluoroalkoxy, nitro or cyano; or R₆ and R₈ together form a 4- to7-membered sultam comprising the nitrogen atom and the S(O)₂ group thatbear them; R₉ represents a halogen atom, a group C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy, orC₁-C₆-fluoroalkoxy; these groups being optionally substituted with agroup OH, C₁-C₆-alkoxy or NR₄R₅; or alternatively R₉ represents a nitrogroup, cyano or NR₄R₅; the sulfur atom(s) of the compound of generalformula (I) optionally being in oxidized form; the nitrogen atom(s) ofthe compound of general formula (I) optionally being in oxidized form;or an acid-addition salt thereof.
 2. The compound of formula (I)according to claim 1, wherein: R₁ is chosen from a hydrogen atom, ahalogen atom and a group C₁-C₆-fluoroalkyl or —Si(C₁-C₆-alkyl)₃; or anacid-addition salt thereof, or a hydrate or solvate thereof.
 3. Thecompound of formula (I) according to claim 1, wherein n is equal to 1;or an acid-addition salt thereof, or a hydrate or solvate thereof. 4.The compound of formula (I) according to claim 1, wherein: Y representsa phenyl, optionally substituted with one or more groups chosen from ahalogen atom and a group C₁-C₆-alkyl or C₁-C₆-fluoroalkyl; or anacid-addition salt thereof, or a hydrate or solvate thereof.
 5. Thecompound of formula (I) according to claim 1, wherein: W represents anoxygen atom; or an acid-addition salt thereof, or a hydrate or solvatethereof.
 6. The compound of formula (I) according to claim 1, wherein: Arepresents the group of formula:

wherein A is chosen from the groups:

these groups being optionally substituted with R₂ and R₃ as defined informula (I) of claim 1; R₂ represents a hydrogen atom; R₃ represents,when it is borne by a carbon atom, a hydrogen atom or a hydroxyl,C₁-C₆-alkyl or oxo group; the C₁-C₆-alkyl group is optionallysubstituted with a hydroxyl or —OC(O)—C₁-C₆-alkyl group; or R₃represents, when it is borne by a nitrogen atom, a hydrogen atom or agroup C₁-C₆-alkyl; or an acid-addition salt thereof, or a hydrate orsolvate thereof.
 7. The compound of formula (I) according to claim 1,wherein: R₁ is chosen from a hydrogen atom, a halogen atom and a groupC₁-C₆-fluoroalkyl or —Si—(C₁-C₆-alkyl)₃; n is equal to 1; Y representsan aryl or a heteroaryl optionally substituted with one or more groupschosen from a halogen atom and a group C₁-C₆-alkyl or C₁-C₆-fluoroalkyl;W represents an oxygen atom; A represents the group of formula:

wherein A is chosen from the groups:

these groups being optionally substituted with R₂ and R₃ as defined informula (I) of claim 1; R₂ represents a hydrogen atom; R₃ represents,when it is borne by a carbon atom, a hydrogen atom or a hydroxyl,C₁-C₆-alkyl or oxo group; the C₁-C₆-alkyl group is optionallysubstituted with a hydroxyl or —OC(O)—C₁-C₆-alkyl group; or R₃represents, when it is borne by a nitrogen atom, a hydrogen atom or agroup C₁-C₆-alkyl; or an acid-addition salt thereof, or a hydrate orsolvate thereof.
 8. The compound of formula (I) according to claim 1,selected from the group consisting of:N-(2,3-Dimethyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[[(3-trifluoromethyl)phenyl]methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;N-(2-Hydroxymethylthiazolo[5,4-b]pyrid-6-yl)-5-trifluoromethyl-1-[(3-methylphenyl)methyl[-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;or an acid-addition salt thereof, or a hydrate or solvate thereof.
 9. Apharmaceutical composition comprising a compound of formula (I)according to claim 1, or a pharmaceutically acceptable salt, hydrate orsolvate of said compound, in combination with at least onepharmaceutically acceptable excipient.
 10. A pharmaceutical compositioncomprising a compound of formula (I) according to claim 2, or apharmaceutically acceptable salt, hydrate or solvate of said compound,in combination with at least one pharmaceutically acceptable excipient.11. A pharmaceutical composition comprising a compound of formula (I)according to claim 8, or a pharmaceutically acceptable salt, hydrate orsolvate of said compound, in combination with at least onepharmaceutically acceptable excipient.
 12. A process for preparing acompound of formula (II):

wherein X₁, X₂, X₃, X₄, n, Y and W are as defined in formula (I)according to claim 1, one from among X₁, X₂, X₃ and X₄ corresponding toa group C-R₁ in which R₁ represents a group -Si-(C₁-C₆-alkyl)₃ asdefined in the general formula (I) according to claim 1 and B representsa group C₁-C₆-alkoxyl; said process comprising reacting a compound ofgeneral formula (VI):

wherein X₁, X₂, X₃, X₄ and W are as defined in formula (I) according toclaim 1 and B represents a group C_(i)-C₆-alkoxyl, with a compound ofgeneral formula (VIII):

wherein Y and n are as defined in the general formula (I) according toclaim 1; and when n is equal to 1, 2 or 3, with a reagent of generalformula (VIII) in which LG represents a leaving group, in the presenceof a base in a polar solvent; when n is equal to 1, 2 or 3, with areagent of general formula (VIII) in which LG represents a hydroxylgroup, in the presence of a phosphine and diethyl azodicarboxylate in asolvent; or alternatively in the presence of a phosphine supported on aresin and diisopropyl azodicarboxylate in solution in a solvent; or whenn is equal to 0, with a reagent of general formula (VIII) in which LGrepresents a leaving group, under an inert atmosphere in basic medium,in the presence of a copper salt in an organic solvent.